TW200848028A - Method for inhibiting proliferation of tumor cells - Google Patents

Abstract

Disclosed are methods for synergistically inhibiting the proliferation of tumor cells by contacting the tumor cells with a MEK inhibitor compound and erlotinib, either sequentially or simultaneously. Also disclosed are methods for inhibiting the proliferation of tumor cells in a human, by administering to the human, sequentially or simultaneously, an amount of erlotinib and a MEK inhibitor compound, wherein the amounts are effective, in combination, to synergistically inhibit the proliferation of the tumor cells in the human.

Description

200848028 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention is directed to compositions that synergistically inhibit tumor cell growth and are useful for the preparation of such compositions. [Prior Art] There are many novel anticancer agents that inhibit molecular targets involved in the path of driving the development, progression and spread of cancer. One such agent is erlotinib, which is a type I human epidermal growth factor receptor/epithelial growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor. Erlotinib is a quinazolinamine having the chemical name N-(3-ethynylphenyl)_6,7-bis(2-decyloxyethoxy)_[quinazolinamine. TARCEVA® (FDA-approved drug) contains erlotinib in the form of the king hydrochloride, which has the following structural formula··

The molecular formula is CnHuNsCU.Ha and the molecular weight is 429 90.

, sodium starch glycolate, sodium lauryl sulfate and titanium dioxide. n-Ltyrosine kinase, which is overexpressed by receptors in a variety of epithelial tumors in which the mutated, ligand-dependent epidermal growth factor receptor is the ErbB family of receptor tyrosine kinases, 128748.doc 200848028 receptor dimerization and Ligand-dependent activation and abnormal activation. Based on the demonstrated survival benefit, erlotinib is approved for the treatment of patients with advanced non-small cell lung cancer who have previously been treated with chemotherapy. The clinical benefit of using anti-EGFR agents has been demonstrated in other tumor types such as head and neck cancer and pancreatic cancer. In tumors, the RAS/RAF/MEK/ERK (MAPK) pathway is an important pathway for the delivery of mitogenic signals from the plasma membrane to the nucleus. A variety of growth factors, such as VEGF, PDGF, FGF, and EGF, transmit a letter, a number via the MAPK pathway. Frequent Ras and Braf mutations have been observed in many human cancers. Ras mutations can be found in 30% of all human cancers, especially pancreatic cancer and colorectal cancer (90% and 50%, respectively). In addition, activation of the ΜAPK pathway is associated with tumor progression and poor prognosis in patients. EGFR and ΜΕΚ share a common downstream signal transduction pathway and play a direct and indirect role in tumor cells. Combining the two agents that target these molecules confers additional clinical benefit and overcomes single resistance. It has now been found that synergistic growth inhibition can be achieved by administering to a combination of erlotinib and a sputum inhibitor a tumor cell that is sensitive to both agents or to a single agent of erlotinib or an inhibitor. Synergistic effects can be seen regardless of the time course of treatment, ie, whether the cells are in contact with both agents simultaneously or sequentially. Analysis of the combined mechanism of action reveals increased apoptosis and phosphorylation of μεκ and phosphorylation. Therefore, the combination of erlotinib and a sputum inhibitor (eg, a substituted betaine) can be provided in tumor therapy. Increased effectiveness. SUMMARY OF THE INVENTION 128748.doc 200848028 Thus, in the 'in-the-state, the present invention is directed to erlotinib and _inhibition: for the preparation of a medicament suitable for inhibiting tumor cell proliferation, which can be used to contain A method in which a tumor cell is contacted with a certain amount of erlotinib and a certain amount of a sputum inhibitor compound in sequence or simultaneously, wherein the amount is effective to inhibit tumor cell proliferation in combination. In another aspect, the invention is directed to the use of erlotinib and a guanidine inhibitor for the preparation of a medicament suitable for inhibiting tumor cell proliferation, the medicament being useful for containing tumor cells sequentially or simultaneously with a certain amount of angstroms A method of contacting rotitan with a quantity of a guanidine inhibitor compound, wherein the amount is effective to inhibit tumor cell proliferation in a combination, wherein the guanidine inhibitor compound is a compound of formula I:

R

Wherein: R1 is selected from the group consisting of bromine, iodine, ethynyl, cycloalkyl, alkoxy, azetidinyl, ethylidene, heterocyclic, cyano, linear alkyl and branched alkyl; R2 Is selected from the group consisting of hydrogen, gas, fluorine and alkyl; R3 is selected from the group consisting of hydrogen and fluorine; and R4 is selected from the group consisting of hydrogen, optionally substituted aryl, alkyl and cycloalkyl; R5 is selected from the group consisting of hydrogen and the following groups: 128748.doc 200848028 R6—C—R8 l7 R7 wherein r6 is selected from the group consisting of hydroxy, alkoxy, cycloalkyl, tri-i-alkyl, alkyl, as appropriate a group of substituted aryl groups and optionally substituted heteroaryl groups; R and R are independently selected from the group consisting of hydrogen, alkyl and tri-alkyl; or R and R7 may together form a cycloalkyl group and R8 Is hydrogen; and a pharmaceutically acceptable salt or ester thereof. In another aspect, the compound of formula I used in the invention has the formula:

Where: is as stated above. In a particular embodiment ' R1 is selected from the group consisting of iodine, ethynyl and cyclopropyl. In certain embodiments 'R2 is selected from the group consisting of hydrogen, gas, and fluorine. In certain embodiments, R3 is hydrogen. In certain embodiments, R5 is r6s9-R8 128748.doc 200848028 and R and R8 are independently selected from the group consisting of hydrogen and sulfhydryl. In certain embodiments, R.sup.4 is an optionally substituted aryl. In certain embodiments, the Ri is selected from the group consisting of iodine, ethynyl, and cyclopropyl. The R is selected from the group consisting of hydrogen, fluorine, and gas, R3 is hydrogen, and R4 is optionally substituted phenyl, R5. For R6-C - R8 R7

And R is optionally substituted phenyl, R7 is methyl, and R8 is hydrogen. Μ may be, for example, a phenyl group substituted with an alkoxy group. In this embodiment, a compound in which Ri is ruthenium and R is a group of far free gas and fluorine is present. In this embodiment, another " The group is a compound substituted with a member selected from the group consisting of 2,3-dihydroxy-propoxy and hydroxy-ethoxy. In another example, the present invention is directed to erlotinib and MEK inhibitors are used for the treatment of the growth of tumor cells that are resistant to erlotinib, and the drug can be used to contain tumor cells in sequence or in the same day. In the method of contacting κ &, Rosini and a certain amount of the compound and its pharmaceutically acceptable salt or ester:

Wherein Ri, H2, R, R4 and R5 in combination are as set forth above; wherein the equivalent is effective in inhibiting tumor cell proliferation. 128748.doc 200848028 In another embodiment, the present invention is directed to erlotinib and a MEK inhibitor for the preparation of a medicament for inhibiting the growth of tumors, cells, and cells resistant to one or more MEK inhibitors. The use of these drugs can be used to include tumor cells in sequence or simultaneously with a certain amount of erlotinib and - quantification! In a method of contacting a compound with a pharmaceutically acceptable salt or ester thereof:

In combination, it effectively inhibits tumor cell proliferation. In another embodiment, the present invention is directed to the use of erlotinib and a MEK inhibitor for the preparation of a medicament suitable for inhibiting the growth of tumor cells in a human body, which may be used to include a certain dose to humans, either sequentially or simultaneously. The amount of erlotinib and a method of a certain amount of a MEK inhibitor compound wherein the amount is effective to inhibit proliferation of tumor cells in humans in combination. In a particular embodiment of G, the MEK inhibitor compound is a hydrazine compound:

Wherein R, R, R, R and R are as defined above; and a pharmaceutically acceptable salt or ester thereof. In another embodiment, the invention is directed to the use of erlotinib and MEK inhibitor 128748.doc 11 200848028 for the preparation of a medicament suitable for inhibiting tumor cell growth in a human, wherein the tumor cells are one or more MEK inhibitors are resistant, and such drugs can be used in a method comprising administering to a human a sequential or simultaneous administration of a certain amount of erlotinib and a quantity of a MEK inhibitor compound, wherein the equal amount is effective to inhibit humans in combination Proliferation of tumor cells in vivo. In a specific embodiment, the MEK inhibitor compound is of the formula];

Wherein R, R, R, R4 and R5 are as defined above; and a pharmaceutically acceptable salt or ester thereof. In another embodiment of the invention, the invention is directed to the use of erlotinib and a mek inhibitor for the preparation of a medicament suitable for inhibiting the growth of tumor cells in a human, wherein the tumor cells are resistant to erlotinib, Drugs can be used to contain certain doses of human or human

^ In the method of erlotinib and MEK inhibitor compounds in the sputum, the 兮笠 a 甲 甲 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 In a win ^^,

In the embodiment of the present invention, the MEK inhibitor compound is a compound of formula I:

Wherein Ri, R2, R3, R4 and R5 are as mentioned above; and their medicinal 128748.doc -12- 200848028 acceptable salt or ester. In another embodiment, the invention is directed to the use of erlotinib and a MEK inhibitor for the preparation of a medicament suitable for inhibiting tumor cell proliferation, the medicament being useful for containing tumor cells sequentially or simultaneously with a certain amount of angstroms In a method of contacting rotitan with a MEK inhibitor compound of sorghum, wherein the amounts are effective to synergistically inhibit tumor cell proliferation in combination. In the present invention, the MEK inhibitor compound of formula I used may be

R1 is selected from the group consisting of bromine, iodine, ethynyl, cycloalkyl, alkoxy, azetidinyl, ethylidene, heterocyclic, cyano, linear alkyl and branched alkyl. a group consisting of gas, fluorine and alkyl; R3 is selected from the group consisting of hydrogen and fluorine; R4 is selected from hydrogen, optionally substituted aryl, optionally substituted heteroaryl, alkyl and cycloalkyl a group consisting of; R5 is selected from the group consisting of hydrogen and the following groups:

Wherein R6 is selected from the group consisting of a hydroxy group, an alkoxy group, a cycloalkyl group, a tris-alkyl group, 127 I., 70, 70, and optionally substituted aryl groups, as appropriate, and optionally a group of substituted heteroaryl groups; independently selected from the group consisting of hydrogen, alkyl, and tri-i-alkyl; or R and R together to form a cycloalkyl group and R8 being hydrogen; and pharmaceutically acceptable Salt or ester. In the present invention, the MEK inhibitor compound of the formula I used may also be

R is selected from the group consisting of bromine, hard, ethyl, cycloalkyl, alkoxy, π-butyl cyano, linear alkyl and branched alkyl, ethyl hydrazino, heterocyclic, cyano Group

R is selected from the group consisting of hydrogen and fluorine; R is selected from the group consisting of hydrogen, optionally substituted aryl, alkyl and cycloalkyl; R5 is selected from the group consisting of hydrazine and the following groups:

Wherein R6 is selected from the group consisting of a thiol group which is substituted by a thiol group, a decyloxy group, a cycloalkyl group, a trialkyl group, an alkane 128748.doc 14 200848028, an optionally substituted aryl group, and optionally a substituted aryl group; And R7 and R8 are independently selected from the group consisting of hydrogen, a home group, and a tridentate group; or R6 and r7 may together form a cycloalkyl group and r8 is hydrogen; and a pharmaceutically acceptable salt or S thereof. In the present invention, the MEK inhibitor compound of the formula I used can be further as follows.

R2〇,

〇 where: 醯 / is selected from the group consisting of 演, 峨, ethynyl, cycloalkyl, alkoxy, ethyl, n, heterocyclyl, cyano, linear low-wei, and branched low-carbon alkyl Group R2 is a group consisting of wind, gas, fluorine and a lower alkyl group; is selected from the group consisting of hydrogen and fluorine; and & freely substituted aryl, low a group consisting of a carbon alkyl group and a cycloalkyl group; R is selected from the group consisting of hydrogen and the following groups: C-R8 128748.doc 200848028 wherein R6 is selected from the group consisting of a hydroxyl group, an alkoxy group, a cycloalkyl group, and a trihalogen low carbon. a group consisting of an alkyl group, a low-stone anti-alkyl group, an optionally substituted aryl group, and optionally a substituted heteroaryl group; R and a trans 8 system are independently selected from the group consisting of hydrogen, a lower alkyl group, and a trihalogenated lower alkane. a group of base groups; or R and R together form a cycloalkyl group and R8 is hydrogen; and a pharmaceutically acceptable salt or ester thereof. In the compound of formula 1, R1 may be selected from the group consisting of iodine, ethynyl and cyclopropyl. In the compound of formula 1, R2 may be selected from the group consisting of hydrogen, gas and fluorine. In the compounds of formula I, R3 can be hydrogen. In the compounds of formula I, R5 can be: R6- and R and R are independently selected

, the work of the W people.

In the compounds of formula I, r4 may be a phenyl group which is substituted with an aryl group and is preferably substituted with an alkoxy group. ^In the compound of formula I, R1 is also a group of free iodine, ethynyl and ciprofloxacin, R2 is selected from the group consisting of hydrogen, g soil, and fluorine, and R3 is hydrogen, optionally substituted Phenyl group, R5 is K

R8 128748.doc • 16 - 200848028 R6 is a phenyl group of (4), and in the compound of formula I, it may be hard and R2 is. Group. K is selected from the group consisting of chlorine and fluorine, wherein R6 can be a phenyl group and R4 is selected from the group consisting of 2,3 "y,,,,,,,,,,,,,, + g phenyl substituted by lanthanum. In all of the above examples, the method 4 is selected from the group consisting of the following groups: hydrogen,

Lower alkyl, C3-6 cycloalkyl, aryl optionally substituted by the following groups: fluoro, hydroxy, as defined by methanesulfonyl substituted lower alkyl, lower alkoxy, substituted by hydroxy Lower alkoxy, dimethyl phosphonate, phosphonic acid, low carbon bad alkyl, morpholinyl, piperazinyl, oxetanyl, -(c = 〇)NRaRb, wherein Ra and Rb are independently Η, depending on the hydroxy-substituted lower alkyl group or R and Rb and the nitrogen atom to which they are attached may form azetidinyl, pyrrolidinyl or morpholinyl, -[0(CH2)2]1.2.〇CH3 ^ _ [o(ch2)2-oc2h5, -[0(CH2)2-〇C2H4〇H, -NH(00)-Re, where Re is a lower alkoxy group or 128748.doc -17- 200848028 N(Rd)2-substituted lower alkyl, wherein Rd is lower alkyl, -nh(c=o)-ch2-alkoxy, -o(ch2)2o-, or selected from thienyl and pyridyl a group of heteroaryl groups. In all of the above embodiments, R6 may be optionally substituted aryl (such as phenyl and naphthyl), and optionally substituted aryl means gas, fluorine, cyano, lower alkyl, Lower alkoxy or trifluoromethyl substituted aryl. In all of the above embodiments, R6 may also be a heteroaryl group substituted by a bromine, a lower alkyl group or a lower alkoxy group (thienyl group, pyridyl group, oxypyridyl group, σ thiol group, taste). σ sitting base). In all of the above embodiments, R6 may also be an aryl-substituted lower alkoxy group. In all of the above examples, R6 may also be methylsulfonyl, _(c=〇)NH2. An aryl substituted lower alkyl group. [Embodiment] The following terms used in the present application have the meanings indicated: • 'Alkyl' represents a linear, branched or cyclic saturated aliphatic hydrocarbon. The alkyl group preferably represents a low carbon base group, that is, a C1_C6 alkyl group and includes a methyl group, an ethyl group, a propyl group, a 'propyl group, a second butyl group, a 2-butyl group, a pentyl group, a hexyl group and the like. The group is as good as the 'low carbon record', preferably the Cl•(10) group, and more preferably the CK3 yard base. An example of a ring-based base is a moiety having 3 to _, preferably 3 to 7 carbon atoms, which includes a cyclopropyl group, a cyclopentyl group and a cyclohexyl group. "二_院基" means that three of the terminal carbon atoms are replaced by halogen. 128748.doc -18- 200848028 , broad base: for example, trifluoromethyl, trichloromethyl, ^•trifluoroethyl, , 1, 1-dipropyl propyl and the like. "trihalo-lower alkyl" means a tri-alkyl group having up to 6 private atoms, preferably 1 to 3 carbon atoms.

Look at the earth base. "" means monovalent, monocyclic or bicyclic, aromatic carbocyclic or heterocyclic, more "-10 member aromatic ring system. Preferred aryl groups include phenyl and naphthyl. Unless otherwise: = month, the aryl group may be, for example, a lower alkyl group, a cycloalkyl group (e.g., a cyclopropyl group), a tri-lower alkyl group (e.g., a trifluoromethyl group), a hydroxyl group, an alkoxy group, In particular, a low-carbon alkoxy group, an alkoxy group substituted by a mono- or di-perylene group, an amine methoxyacetamide group, a dimethylaminoethylamine group, a halogen (for example, a mouse, a milk or a hair) , a benzene 16 derivative, a guanamine derivative of an aniline derivative, and a methane % mercapto mono-, di- or tri-substituted. Heteroaryl means a monovalent aromatic 5 or 6 membered monocyclic ring containing one, two or three ring heteroatoms selected from N, hydrazine or S, the remaining ring atoms being C. Preferably, the 5 or 6 membered heteroaryl ring contains one or two ring heteroatoms. A 6-membered heteroaryl group is preferred. Examples of heteroaryl moieties include, but are not limited to, thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, indolyl, tetrazolyl, quinolinyl, imidazolyl, Oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxy-pyridyl, indole, 2, oxadiazole or 1,3,4-oxadiazolyl. Unless otherwise specified, a heteroaryl group can be optionally, for example, a lower alkyl group, a cycloalkyl group (e.g., a cyclopropyl group), a trihalo lower alkyl group (e.g., a difluoromethyl group), a hydroxyl group, an alkoxy group, In particular, a lower alkoxy group, a mono or dihydroxy substituted alkoxy group, an etidinyl group, a decyloxyethylamino group, a dimethylaminoethylamino group, a cyclin (for example, fluorine, gas or bromine) An aniline derivative, a guanamine derivative of an aniline derivative, and a methanesulfonyl monosubstituted, disubstituted or 128748.doc -19-200848028 trisubstituted. When two or more substituents are present on the aromatic ring or the heteroaryl ring, they are also present in the y form. Such fused rings include, but are not limited to, 3, a mesotylene, a dioxyphenyl group, and a 3,4-extended ethyldioxyphenyl group. Soil A hetero atom, meaning an atom selected from N, 〇 and s. '丨 Heterocyclic 丨' means having four to one king, one stone anti-atom and at least one hetero atom group.

''Alkoxy or lower alkoxy" means any of the above lower alkyl groups attached to an oxygen atom. Typical low carbon filament groups include methoxy, ethoxy, isopropoxy or propoxy, butoxy, cyclopropylmethoxy and the like. Further included in the meaning of the calcined base are a plurality of silk-based side chains such as ethoxyethoxy, oxyethoxy, methoxyethoxyethoxy, methyloxetanylmethoxy and Similar group. Also included are substituted alkoxy side chains such as ethoxycarbonyl, m propoxy, dimethylaminoethoxy, diethylaminoethoxy, galmethoxy, dimethoxy 4 Mercaptomethoxy, amine methylmethoxy, methyl and dimethylamine methyl methoxy, amine carboxylic acid ethoxy, methyl and dimethylamine methyl decyl ethoxy, bamboo bite Ketomethyl ethoxy group, pendant oxypyrrolidinyl ethoxy, bishydroxyethylamine carbaryl methoxy, morpholinyl methoxy, morpholinyl ethoxy, piperazinyl methoxy Base, piperazinyl ethoxy, lower alkyl piperazine ethoxy, pendant oxy-pyrrolidine ethoxy and the like. ''Pharmaceutically acceptable esters," refers to the conventional esterification of a carboxyl group, the bioavailability and properties of the ester-retained compound and its decomposition into the corresponding activity in vivo (in an organism) carboxylic acid. 128748.doc -20 - 200848028 Information on the use of esters and esters for the delivery of pharmaceutical compounds is available in Design of Prodrugs. Bundgaard Hans (Elsevier, 1985). See also Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th ed. 1995), pp. 108-109; Krogsgaard-Larsen et al., Textbook of Drug Design and Development (2nd ed. 1996), pp. 152-191. ''Pharmaceutically acceptable salt'" means a conventional acid addition salt or test which retains the biological effectiveness and properties of the compound of the present invention and is prepared from a suitable non-toxic organic or inorganic acid or an organic or inorganic base. Salt-forming. Acid addition salt samples include those acid addition salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, aminosulfonic acid, scalylic acid and nitric acid, and are derived from such An acid addition salt of an organic acid of toluene, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, trifluoroacetic acid, and the like. The base addition salt samples include the base addition salts derived from ammonium hydroxide, potassium hydroxide, IL sodium oxide, and a quaternary ammonium hydroxide such as tetramethylammonium hydroxide. Pharmaceutical compounds (ie, drugs) Chemical modification to salt is a technique well known to pharmaceutical chemists for obtaining improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, for example, eight old "Essentials, Pharmaceutical Dosage F〇rms". And Drug d y y

Systems (6th Edition 1995), pp. 196 and 1456-1457. "Pharmaceutically acceptable, for example, a pharmaceutically acceptable carrier, excipient, etc., means that it is pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered. "Substituted in an aryl or heteroaryl group, meaning that the substitution may occur 128748.doc -21 - 200848028 at one or more positions and unless otherwise stated, the substituents at each substituent are independently Select from the options specified. By 'therapeutically effective amount or effective amount' is meant an amount at which at least one of the specified compounds significantly inhibits proliferation and/or prevents differentiation of human tumor cells, including human tumor cell lines. Examples of MEK inhibitors suitable for use in the practice of the invention include ( But not limited to) they are not disclosed in US Patent 6,455,582, 6,835,749, 7, 〇19, 〇33, 6,310, _, 65G6 798, 6 821 963, 6,44G 966, 6,750,217, 7, 〇〇ι,9〇5 MEK inhibitors of 6, 148, 004, 6, 960, 914, 6, 492, 363 and 6, 545, 03 0 and ct publication No. WO 00/41505. MEK inhibitors of formula I:

Wherein: R is a group consisting of far more free bromine, iodine, ethynyl, cycloalkyl, alkoxy, azetidinyl, ethylidene, heterocyclic, cyano, linear alkyl and branched alkyl; R2 Selected from the group consisting of argon, gas, fluorine and alkyl; R3 is selected from the group consisting of hydrogen, chlorine and fluorine; R is a group of 4 free hydrogen, optionally substituted aryl, alkyl and cycloalkyl groups , 128748.doc -22- 200848028 R5 is selected from the group consisting of hydrogen and the following groups: R6—C—R8 wherein R is selected from alkyl, alkoxy, (iv), optionally substituted alkyl, a group of substituted aryl groups and optionally substituted heteroaryl groups; R and R are independently selected from the group consisting of hydrogen and optionally substituted alkyl groups; or R6 and R7 may together form a cycloalkyl group. And R8 is hydrogen; and pharmaceutically acceptable salts or esters thereof are particularly suitable for use in the process of the invention. These MEK inhibitor compounds can be prepared according to the general procedure set forth below: Η〇^γΝ-ΡΘ1 _^ X^V^PGl R5 Step 1 R5

3 R4 7 h〇Y^n-pg2 I H , Step 4

5 Step 3

R1 Vulture> R3 R5 〇

H2 Step 6 128748.doc 1 -23- 200848028 Step 1: The compound containing the α-amino acid functional group of the formula 2 is converted into a reactive deuterated material of the formula 3 in the second step suitable for the synthesis sequence. Step 1 is most conveniently carried out with a protecting group (pG1) ia amino acid on the alpha amine nitrogen. A suitable choice for the protecting group PG1 is such that the a-amine nitrogen is inert to the reaction conditions employed during the synthesis sequence step and during the second step, but may not cause the remaining compound when exposed to the conditions required to remove the sulfhydryl group. In the case of improper modification, the protecting group is removed during the synthesis sequence step 3. A preferred choice of protecting group pGi can be found in organic chemistry textbooks (e.g., Pr〇tectWe Gr〇ups than Organic Synthesis, Theodora W. Greene et al.), original chemical literature, or generally known to those skilled in the art of organic synthesis. In particular, a urethane-based protecting group (e.g., a third butoxycarbonyl group and a 9H-fluorenyl-9-ylmethoxycarbonyl group) is preferred, but other amine protecting groups may also be effective. The choice of the reactive oximation agent forming Formula 3 depends on the compatibility with the potentially reactive functional groups present elsewhere in the compound of the formula] and the formula 3 for the deuteration of the aniline derivative of Formula 4 The reactivity and selectivity of the agent. This reaction produces the desired amide linkage present in the compound of formula 5. The typical reactivity &&> agent that can be used in step 2 is a brewing base (3, χ = _ 素) and an acid anhydride (3, X = 〇 - C (0) R). The preferred choice for the oxime of the formula 3 is fluorenyl halide, especially fluorenyl fluoride (3, X = fluorine), decyl chloride (3, χ = = gas) and mercapto bromine (3, χ = bromine ). Other options for the oxime of Formula 3 may also be suitable for use in Step 2 and will be apparent to those skilled in the art of organic synthesis. In the case where the compound of the formula 2 contains a palmitic center at the ruthenium carbon, the preferred stereochemistry is S. Step 2: The aniline derivative of the formula 4 is combined with a preformed hydrazine of the formula 3 128748.doc -24-200848028 to form a hydrazine derivative of the formula 5. It will be apparent to those skilled in the art of organic synthesis that, using known peptide coupling reaction techniques, it is possible to prepare a compound of formula 5 directly from a compound of formula 2 and formula 4 without prior formation of a reactive oximation agent of formula 3. Typical coupling agents which can be used to directly convert a compound of Formula 2 and Formula 4 into a compound of Formula 5 include diimine-based reagents such as dicyclohexylcarbodiimide, (3-dimethylamino)- Propyl)-ethyl-carbodiimide hydrochloride; or based on reagents such as cesium hexafluorophosphate benzotriazole-based N, N, N', N'-tetramethyl hydrazine or six Bismuth fluorophosphate_stupidyl triazole->!,;^,:^,;^|-bis(tetramethylene)fluorene. Alternative peptide coupling reagents can also be effective in the performance of this transformation. The selection of alternative peptide coupling reagents can be made by reference to the original chemical literature or generally known to those skilled in the art of organic synthesis. Step 3: This step in the synthesis sequence requires removal of the protecting group PG1 from the compound of Formula 5 to form the amine-containing compound of Formula 6 in the subsequent processing. As noted above, the choice of protecting group PG1 and the conditions for removal of PG oxime during step 3 is subject to other potentially reactive functional groups present in the compound of formula 5 and to the starting material or product of the reaction (ie, Others in the compounds of the formulae 5 and 6) avoid the effects of the requirements of the improper reaction. In the case where the amine protecting group PG1 present in the compound of the formula 5 is a third butoxycarbonyl group, it can be shifted under acidic conditions such as trifluoroacetic acid in di-methane or hydrochloric acid in dioxane. In addition to the protecting group. Removal of the third butoxycarbonyl group under acidic conditions initially releases the corresponding salt of the compound of formula 6 which, upon treatment with a base, releases the free amine of formula 6. In the case where the amine protecting group PCH present in the compound of Formula 5 is 9H-g-9-ylmethoxycarbonyl, the basicity of piperidine in dioxane such as 128748.doc -25-200848028 can be obtained. The protecting group is removed under conditions. Step 4 · The compound of the formula 8 is obtained by combining an amine of the formula 6 with a compound containing an α-amino acid functional group. Step 4 is most convenient &> is carried out on a compound of formula 7 having a protecting group (PG2) ia amino acid on the alpha amine nitrogen. The criteria for selecting the protecting group PG2 are the same as those for the step of selecting the protective substrate. More specifically, the protecting group based on the amine group (IV) (e.g., the second butoxycarbonyl group) is preferred, but other amine protecting groups may also be effective. In the case where the compound of formula 7 contains a palmitic center, the preferred stereochemistry is R. Step 5: This step in the synthesis sequence requires removal of the protecting group PG2 from the compound of formula 8 to form The amine-containing compound of the formula 9 is subsequently subjected to a synthesis sequence. The selection of the conditions for removing the protecting group PG2 from the compound of the formula 8 is based on the chemical reactivity of the protecting group PG2 and the reaction occurring in the step 5 The alkaloids and reactivity of other precursors in the starting materials and products (that is, the compounds of the formulae 8 and 9, respectively). In the case where the amine protecting group PG2 present in the compound of the formula 8 is a third butoxycarbonyl group The protecting group can be removed under acidic conditions such as trifluoroacetic acid in dichloromethane, hydrochloric acid in dioxane or pure formic acid. The initial release of the third butoxycarbonyl group is removed under acidic conditions. The corresponding salt of the compound of the formula 9 can be used to release the free amine of the formula 9 from the salt after treatment with a base. v. 6 · The compound of the formula 如 as claimed in the present invention may be carbon ruthenium or equivalent By cyclization in the presence of an anthracene (ie, a carbonyl group is directly attached to A displaceable group) is obtained from a compound of formula 9. Achieving cyclization of a compound of formula 9 to pass 128748.doc • 26-200848028 The preferred reagent for the compound of formula 1 is a gas-gas trisole, which is in the reaction mixture. Charcoal gas in two fields in the field. The compound of formula 9 is cyclized with triterpene phthalate, which is generally faster and more efficient, at low temperatures (< generations) and under carefully controlled amounts. The acid formed during the cyclization is neutralized, but the formation of a base which is potentially unstable in the formation of the urinary urea ring and the occurrence of an unnecessary isomerization is prevented.

It will be apparent to those skilled in the art of organic synthesis that the substituents labeled as R1R5 or the substituents included in the definition thereof in the compounds shown in the scheme are in a chemically reactive group and are themselves chemically reactive. Where a group or a chemically reactive group is present, other modifications to the compounds of Formulas 1 to 9 containing such reactive groups may be possible. The time point at which the chemically reactive group is modified in the synthesis sequence can be selected such that the newly processed group is chemically inert to the reagent to be used during the remaining steps of the synthesis sequence and does not interfere with the 漭 aluminum 彳 by _ 卞馊 &quot ;, the remaining steps of the synthesis sequence not in L耘1. Alternatively, if the newly processed group is not chemically inert or may interfere with the remaining steps of the sequence, it may be necessary to temporarily mask the reactive functional group with appropriate protecting groups or to derivatize the functional group into the remaining transformation in the synthetic sequence. The portion that is stable and will be present in the final product of the reaction sequence. If a protecting group which is not required in the final compound of the general formula is introduced, it can be regarded by the nature of the protecting group used, under the condition of 80% of the order of being retained in the stream, or by the synthesis to °. The protecting group is removed.彳 "External deprotection step The reaction conditions of the above reaction may vary to some extent. The method of carrying out the above reaction and process will be based on the present disclosure for the general technique 128748.doc -27- 200848028 = obvious or similarly An example is derived. The starting materials are either commercially available or can be prepared by methods analogous to those described in the Examples. The compounds of Formula 1 and salts thereof have at least two asymmetric carbon atoms and thus a mixture of stereoisomers The various isomers can be separated by a known method (e.g., chromatography). The treatment of the compound of the formula I of the present invention is tian, 焱心心明 for prevention, alleviation or modification: disease or: long treatment of the subject It is within the skill of the art to be effective in the survival of the compound. The therapeutically effective amount or dose of the compound of the formula can be determined in a manner known in the art. It will be adjusted according to individual needs in the treatment of specific compounds, the route of administration, the condition to be treated and the specific conditions involved. In general, the weight is about 70 kg. Human! Oral or parenteral administration / L,,, mg to about 1G, _ mg, preferably about _ mg to about _: g dose of female sputum should be appropriate 'although the upper limit can be exceeded when specified. The dose of the mother can be administered in a single dose or in divided doses, which may be one or more..., main:: and or for parenteral administration. The fly-human rapid injection or continuous infusion form is suitable for the practice of the present invention. The system can be internally administered, such as oral extracts, coated lozenges, sugar-coated pills, hard and soft gelatin capsules, Loose, emulsion or suspension, 妳g 襄4, The administration of τ (for example, in the form of a nasal spray) or, for example, in the form of a suppository, may be administered parenterally, such as intramuscularly or intravenously (for example, in the form of an injection solution). (For example, it is also in the form of 7 holes or oil.) 128748.doc -28- 200848028 It can be used in the manufacture of tablets, pharmaceutically inert, prosthetic agents, sugar-coated pills and hard gelatin capsules. =5 adjuvant to process the compound of formula (1) and its substance, microcrystalline cellulose, two r: r,, ^ ^ ', biological, ethpyrazine 、, 庐 庐: ketone, talc, stearic acid or its salt, etc. are used as (for example): syrup, syrup and hard gelatin capsules Such adjuvants. Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-quotes, and liquid polyols, etc. Suitable for making solutions and sugars: Water, polyol, #^庶糖, invert sugar, glucose, etc., and suitable adjuvants for the main solution are, for example, water, alcohol, polyol, glycerin, vegetable oil, etc. Suitable adjuvants for suppositories are (for example) Day, or hardened oil 1, fat, + solid or liquid polyol, etc. Suitable adjuvants for topical preparations are glycerin, semi-synthetic and synthetic glycerin, chlorinated oil, liquid bad, liquid stone, liquid fatty alcohol , alcohol, polyethylene glycol and cellulose derivatives. The pharmaceutical preparation may contain a preservative, a solubilizing agent, a viscosity increasing substance, a sputum blistering agent, an emulsifier, a sweetener, a coloring agent, a fragrance, a salt for osmotic pressure, a buffering agent, a masking agent. Or antioxidants. It may also contain other therapeutic substances. The following examples are intended to illustrate the preferred embodiments of the invention, but are not intended to limit the scope of the invention. Example 1 (2S,3S)I(4-Mo-phenyl)-2-[(R)-4-('methoxy-phenyl)-2,5-di-oxy-imidazolidin-1-yl ]-3-phenyl-butanamine 128748.doc -29- 200848028

Step 1: at -35t, under (2S,3S)_2_t-butoxycarbonylamino-3-phenyl-butyric acid (838 mg, 3〇mm〇1) in a dry argon atmosphere Anhydrous pyridine (255, 3 15 and cyanuric dichloride (3 75 μί, 4.5 mmol) was added to the solution in formazan (10 mL). The mixture was stirred for 15 hours while maintaining the temperature at -35 and -25. (: between. Add less ice to the reaction mixture and vigorously stir the mixture for 15 minutes. The organic layer is decanted from the aqueous solution and the aqueous layer is extracted with di-methane (2×l 〇mL). Wash with ice-cold water (15 mL), dry over NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Step 2: Add to 4-bromoaniline (97% purity) (177 mg, 1.0 decylmorpholine (220 pL, 2.0 mmol) in anhydrous tetrahydrofuran (3 mL) 1 _Fluoroyl-2-phenyl-propyl)-aminobutyric acid tert-butyl ester (~1.5 mmol) in anhydrous tetrahydrofuran (2 mL + 1 mL to rinse into the addition funnel in the ruthenium mixture) a solution and a catalytic amount of dimethyl-pyridyl-4-yl-amine. The mixture was heated to reflux at dry atmosphere for 3 hours and then cooled to ambient temperature. The reaction mixture was concentrated in vacuo and the residue was dissolved. The organic solution was washed successively with water (one time), EtOAc EtOAc EtOAc (EtOAc) (13,28)-1-('Mo _Benzene 128748.doc -30- 200848028 amide methyl)-2-phenyl-propanone 1. ft rn λ/λ /-Λ- 円丞 円丞 J- The third butyl carbamate (530 mg) was used in the next step without further purification. LC-MS: mp. Step 3 · At 0C, under a dry argon atmosphere, (ls, 2s) small (4_ _ _ phenylaminocarbamimidyl)-2-phenyl-propyl] carbamic acid tert-butyl ester (53 Trifluoromethane (8 mL, 1 〇 8 mmol) was added to a solution of EtOAc (1 mL) in dichloromethane (12 mL). The residue was suspended in ice-cold water in vacuo. The aqueous suspension was neutralized with a saturated aqueous solution of sodium bicarbonate (丨 2 mL), and then extracted with dioxane (di-man). The extract was dried over sodium sulfate, filtered and taken in vacuo to give (2S,3S)-2-amino](4-bromo-phenyl)-3-phenyl-butanamine (334 mg) without further Purification can be used in the subsequent steps. LC-MS ·· C16H18BrN20+ observation mass (m+H+) = 333/335; calculation Quality: 333/335. Step 4: (2S,3S)-2-Aminobromo-phenyl)-3-phenyl-butanamine (167 mg, =0.5 mol) at TV, TV-dimethyl ketone at 0 °C (R)-Tertibutoxycarbonylamino-4-methoxyphenylglycine (155 mg, 0.55 mmol) was added to the solution in the amine (3 mL) (according to Hyun, Μ·Η· et al. , j [iq Chrom· & Rel· Technol· 2002, 25, 573-588 preparation), TV, TV-diisopropylethylamine (3 50 pL, 2.0 mmol), benzotrimethylene (82 mg, 0.6 mmol), hexafluoroantimonate-benzotrimethyl-tetramethylguanidine (227 mg, 0.6 mmol) and the catalytic amount of two 128,748.doc -31 - 200848028 methyl- Acridine-4-ylamine and the mixture was stirred under a dry argon atmosphere and allowed to warm to ambient temperature overnight. The reaction mixture was poured into ice/water (5) EtOAc. EtOAc (EtOAc) (EtOAc) And in the vacuum, Chen Chen. The crude product was purified by chromatography on silica gel eluting with EtOAc EtOAc (EtOAc) Methoxy-phenyl)-methyl l-aminocarboxylic acid tert-butyl ester (154 mg, 52%). LC-MS : Observed mass of C30H33BrN3O5 · 594/596 ; Calculated Quality: 594/596. Step 5: [[(ls: Μ)"#- bromo-phenylaminoindenyl)-2-phenyl-propylaminecarbamyl; methoxy in a dry argon atmosphere at 〇 °C Add a solution of trifluoroacetic acid (6 mL, 81 mm 〇1) to a solution of trimethyl hydrazide (15 mg, 0.25 mmol) in dichloromethane (10 mL) And the mixture was mixed at 0 C for 1 · 5 hours. The reaction mixture was concentrated in vacuo and the residue was suspended in ice cold water. The aqueous suspension was neutralized with a saturated aqueous solution of sodium bicarbonate (12 mL) and then extracted with dichloromethane. The combined organic extracts were dried <RTI ID=0.0>(Na~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Acetylamino] o-phenyl)-3-phenyl-butylamine (124 mg) was used in the next step without further purification. LC-MS: Observed mass of C25H26BrN303+ (M+H+) ·· 496/498; calculated mass 496/498. Step 6: At _35 ° C, under a dry argon atmosphere, under stirring, pass 1 〇 128748.doc -32- 200848028 to di-phosgene (20 pL, 0.17 mmol) at 1:1 v/v Add dropwise to the solution in toluene/tetrahydrofuran (16 mL total) (28,38&gt;2_[(11)_2_amino-2_(4·decyloxy-phenyl)-acetamido]_Ν·( 4_Bromo-phenylphenyl-butanamine (120 mg, 〇·24 mm〇1) and hydrazine, hydrazine/diisopropylethylamine (21 ,, i 2 mmol) in tetrahydrofuran (8 mL) After a further 45 minutes, ice is added and the reaction mixture is stirred vigorously and warmed to ambient temperature. The reaction mixture is poured into water, extracted with ethyl acetate (twice) and the combined organic layers are successively water ( Wash twice with 2% aqueous hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and brine, then dried over sodium sulfate, filtered and concentrated in vacuo. /v hexane/ethyl acetate elution purification. The isolated product was dissolved in a small volume of methane methane and then precipitated by dropwise addition to a vigorously stirred large volume of petroleum ether.

HRMS: Observation of CMHhBrNsCV f #(Μ+Η+): cut ι〇2ΐ; calculation quality: 522.1023. Example 2

128748.doc -33- 200848028 was prepared by the same method as described in Example 1, except that (1) 4-bromo-2-fluoroaniline was used in place of 4-bromoaniline in step 2 and (Π) in step 4. (R)-Tertibutoxycarbonylamino-[4-((S)-2,2-diindenyl-[1,3]dioxolan-4-ylmethoxy)-benzene Substituting -(Ac)-tert-butoxycarbonylamino-4-methoxyphenylglycine. Prepared and used as described in Example 11 4 and used (R)-di-butoxyaminoamino-[4-((S)-2,2·dimethyl-[1,3]dioxolane- 4-Methoxyoxyphenyl]-acetic acid HRMS: Observed mass of C28H28BrFN306+ (M+H+): 600.1137; Calculated by mass: 600.1140. Example 3 (2S,3S)-7V-(4-bromo-2- Gas-phenyl)-2-{(R)-4-[4-(2-hydroxyethyloxy)-benzyl]-2,5-one-side oxy-miso-decyl-1-yl}- 3 - Stupid-butylamine

Step 1: 4-Bromo-2'-aniline (325 mg, 1.58 mmol) and (S,S)-2-tert-butoxycarbonylamino group in pyridine (5 mL) _3_ Phenyl-butyric acid (440 mg, 1.58 mmol) was cooled to _3 (rc. nitrous oxide (〇 158 mL, 丨.7 mm 〇 1) was added and stirred at -2 (TC for 2 hours). Pour into ice water and extract with ethyl acetate (3 times). The combined organic extracts were washed with water, brine, dried over sodium sulfate and concentrated in vacuo. And the addition of sulphonic acid (1) mol) was continued for 2 hours at 0 ° C. The mixture was evaporated and the residue 128748.doc -34 - 200848028 was dissolved in diethyl ether. And extracted with diethyl ether. The organic extract was washed with brine, dried over sodium sulfate and evaporated to give (2S,3S)-2-amino-7V-(4-bromo-2- phenyl-phenyl)-3-benzene Butylamine (325 mg, 55%) 〇Step 2: (TCS (2S,3S)_2-amino]_(4_bromo-2-chloro-phenyl)_3_ stupyl-butyr &amp;amp Amine (320 mg, 0·87 mmol) dissolved in N,N-dimethylformamide (3 mL) Add (R)-tert-butoxycarbonylamino-[4_(2_t-butoxy-ethoxy)-phenyl]-acetic acid (320 mg, 0.87 mmol) (if preparation (r)_ Preparation of the second butoxycarbonylamino-{4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl-acetic acid as described in Example 48, except that 2_ (2_Bromo-ethoxy)-2-methyl-propane instead of 2-(2-bromo-ethoxy>tetrahydropyran), diisopropylethylamine (〇·71 mL, 2 〇 Mm〇l), I hydroxybenzotriazole (82 mg, 0.6 mmol), phenyl trifluorophosphate, tetramethyl hydrazine (227 mg, 0.6 mmol). After 30 minutes, the reaction mixture was poured into ice. / Water (20 mL), extracted with EtOAc (EtOAc (EtOAc)EtOAc. Concentration to give [[(lS,2S)_l-(4-bromo-2-chloro-phenylaminoindenyl)_2-phenyl-butylaminecarbamyl]-((R) as a white solid -4-(Tertidinoxy-ethoxy)-phenyl]methyl]-carbamic acid tert-butyl ester (560 mg). The ester was suspended in acetonitrile (5 mL). Add 4 The ruthenium chloride in dioxane (2 mL) was stirred and the mixture was stirred for 5 hrs. The mixture was evaporated and dried with diethyl ether/hexane. Dissolve between methyl chloride. The organic layer was separated and washed with brine and dried over sodium sulfate. Evaporation of the solvent gave [[(lS,2S)-l-(4-bromo-2-a-phenylamine fluorenyl)-phenyl-butylamine hydrazide as a white solid, 128, 748.doc -35 - 200848028 Mercapto H(R)-4-(t-butoxy-ethoxy)-phenyl)-methyl]-amino decanoic acid (346 mg, 72%) 0 Step 3 · Under -78C 'will [[(lS, 2S)-l-(4 - oxa-2 - gas-phenylamine fluorenyl)-2-phenyl-butylamine carbazino]-((R)-4-(third Butoxy-ethoxy-phenyl)-indenyl]-carbamic acid (344 mg, 0.56 mmol) and diisopropylethylamine (0.40 mL, 2.25 mmol) were added to tetrahydrofuran (5 mL) and toluene Diphosgene in (5 mL) (47 μί, 0.39 mmoGt. The mixture was stirred and allowed to slowly warm from -78 °C to -30 °C over 1.5 hours and then diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The residue was then triturated with hexane to give #-(4-bromo-2- phenyl-phenyl)-2-{4-[4-(2- Third butoxy-ethoxy)-phenyl]_2,5-di-oxy-imidazolidinyl-1-yl}-3-phenyl-butanamine (300 mg, 84%). Step 4: #-(4-Mo-2-chloro-phenyl)-2-{4-[4-(2-Terti-butoxy-ethoxy)- Base 2,5-di- oxy---------------------------------------------------- Add dimethyl sulphur base gas (〇·36 mL, 2.8 mmol), followed by sodium iodide (3 52 mg, 2.35 mmol). Mix the mixture in 〇. It was then diluted with ethyl acetate. The mixture was washed with aq. sodium hydrogen sulfate, washed with brine, dried over sodium sulfate and evaporated Chloro-phenyl)-2-{4_[4-(2-hydroxy-ethoxy)-phenyl]-2,5-di-oxy-imidazole-1-yl}_3_phenyl-butane Amine (210 mg, 76%) HRMS: Observed mass of C27H26BrClN305 + (m+H+): 586.0739; count 128748.doc -36-200848028 Calculated mass: 586.0739. Example 4 (S)_, (4-iodo-benzene Base)_2-[(R)-4-(4_decyloxy-phenyl)_2,5•di-side oxyimidazolidine-1-yl]-3-phenyl-propanamide

Prepared by the same method as described in Example 1, except that (1) Substituting (S)-2-tert-butoxycarbonylamino-3-3-phenyl-propionic acid in step 1 (2S, 3S) -2-t-butoxy-Wikiylamino-3_phenyl-butyric acid, (丨丨) used 4-iodoaniline instead of 4-bromoaniline in step 2 and (iii) (S)-2 -Amino-((A-phenyl)-3-phenyl-propionamide trifluoroacetate is isolated in step 3 and in 1.0 equivalents of triethylamine and (3-dimethylamino-propyl The ethyl ethyl-carbodiimide hydrochloride is used as a coupling reagent instead of ruthenium hexafluorophosphate-benzotriazine _ _ _ _ a 7V, W, W-tetradecyl sulfonium salt in the case of step 4 HRMS : observed mass of C25H23IN304 + (M+H+): 556.0726 ; calculated mass: 556.0728. Example 5 (2S,3S)-7V-(4-A-phenyl)-2-[(R)-4-( 4-decyloxy-phenyl)_2,5-di-oxy-imidazolidin-1-yl]-3-phenyl-butanamine

128748.doc -37- 200848028 by substituting the same method as described in Example 1, except that 4-iodoaniline was used in place of +2 in place of 4-bromoaniline and in step 4 (3) _Di-di-propyl-propyl)-ethyl-carbodiimide hydrochloride is used as a coupling reagent instead of I 2 squaric acid (9-benzoquinone-tris-yl-iV, 7V, 7V', TV IV Methyl | urine HRMS: C26H25IN3〇/ observation quality (M+ir): 57〇〇883 quality: 570.0884. #例6

(2S,3S)-2- {(R)-4-[4-(2-hydroxy-ethoxy)-phenyl]_2,5-di-oxyl_17 m olanzapine-1 -yl} -7V-(4-A-phenyl)-3-phenyl-butylamine

Prepared by the same method as described in Example 48 except that (1) in step 2, 4-iodoaniline was used in place of 2-fluoro-4-iodoaniline and (ii) in step 4 (3-dimethyl Amino-propyl)-ethyl-carbodiimide hydrochloride was used as a coupling reagent instead of hexafluororesidic acid (9-benzotris-s-diyltetramethylhydrazine. HRMS: C27H27IN3〇5 + observation Mass (M+H+): 600.0987; Calculated mass: 600.0990 ° Example 7 (28,38)-2-{(&amp;)-4-[4-(2-ethoxy-ethoxy)-phenyl] -2,5-di-oxy-imidazole-1-yl, (4-iodo-2-phenyl)-3-phenyl-butanamine 128748.doc •38- 200848028

Prepared by the same method as described in Example 1, except that (1) 4-iodoaniline was used in place of 4-bromoaniline in step 2 and (R)-t-butoxy group was used in step 4. The carbonylamino group _{4_ethoxy-ethoxyphenyl phenylacetic acid replaces (R)-t-butoxycarbonylamino-4-tetramethoxyphenylglycine. (R)-Tertibutoxycarbonylaminoethoxy-ethoxy]-phenyl-acetic acid was prepared as described in Example 48, except that 丨-bromo-2-ethoxylate-ethane was used instead. 2_ (2-Bromo-ethoxy)-tetrahydro bridging domain. HRMS : observation mass of C29H31IN305 + (M+H+) · (iv) 13〇5; calculation Quality: 628.1301. Example 8 (2S,3S)j-(4-iodo-phenylmethoxy-ethoxy)-ethoxy]-phenyl b 2,5-di-oxy-imidazolidinylphenyl-butanamine

Prepared by the same method as described in Example 7, except that (R)-t-butoxycarbonylamino-{4-[2-(2-methoxy-ethoxy)-B was used. Oxy]-stupylacetic acid replaces (R)-t-butoxycarbonylamino-{4•ethoxy-ethoxy]-phenyl}-acetic acid. Prepared as described in Example 48 (H): butyl oxide 128748.doc -39- 200848028 carbonylamino-{4-[2-(2-methoxy-ethoxyl.ethoxy)- Phenyl}-acetic acid' except for the use of 1-(2-bromo-ethoxy)-2-methoxy-ethane instead of 2-(2-bromo-ethoxy)tetrahydropyran. HRMS: C30H33IN3O6+ Observed mass (M+H+): 658.1410; calculated mass: 658.1409. Example 9 (2S,3S)-7V-(4-iodo-phenyl)-2-[(R)-4-(4-methylamine Methyl methoxy-phenyl)-2,5.di-oxy-imidazolidin-1-yl]-3-phenyl-butanamine

Prepared by the same method as described in Example 5, except that in the step 4, (R)-t-butoxycarbonylamino-(4-methylamine-mercapto-methoxy-benzene) was used. ())-acetic acid replaces (R)-t-butoxycarbonylaminomethoxyphenylglycine. Preparation of (R)-Tertibutoxycarbonylamino-- by a method similar to that used in the preparation of (R)-t-butoxycarbonylamino-4-methoxyphenylglycine in Example 1. 4-Methylamine-methyl methoxy-phenyl)-acetic acid, with the exception that 2-oxomethyl-acetamide was used in place of iodoformamidine. HRMS : observed mass of C28H28IN4〇5 (M+H+) : a? 1〇96 ;calc. Quality: 627.1099. Example 10

128748.doc -40- 200848028 guanamine

Prepared by the same method as described in Example 1, except that (1) 4-iodoaniline was used in place of 4-bromoaniline in step 2 and (ii) butadiene-1-yl-2-yloxy group was used. _Ethoxy)·Phenyl]-Tertibutoxyamino-acetic acid instead of (R)-Tertibutoxycarbonylamino-4-methoxyphenylglycine. Preparation of (11) 44-(2-azetidine_丨_ by a method similar to that used in the preparation of (R)-t-butoxycarbonylamino-4-tetramethoxyphenylglycine in Example 1. Base 2_sideoxy-ethoxy)-phenyl]-tert-butoxycarbonylamino-acetic acid, with the exception of using 1 - ° σ σ 定 -1 -1 - yl 2- ethane - acetamidine Replace the simmering. HRMS · Observational mass of C30H30IN4O5 (Μ+Η+) : 653.1258 ; Calculation Quality: 658.1256. Example 11 (28,3 8)-7\^(4-Carbon-phenyl)_2-{(foot)-4-[4-(2-?-lin_4-yl-2-sideoxy-ethoxylate Base)-bensyl]-2,5--sideoxy-imidazole-_1-yl}-3-phenyl-butylamine

Prepared by the same method as described in Example 1, except that (1) 4-thromaniline was used instead of 4-bromoaniline in step 2 and (ii) (R)_Third 128748.doc-41 - 200848028 Oxycarbonylamino[4-(2-morpholin-4-yl-2-yloxy-ethoxy)-phenyl; acetic acid instead of (R)-t-butoxycarbonylaminomethoxy Phenylglycine. Preparation of (R)-t-butoxycarbonylamino group by the method similar to that used in the preparation of (R)-t-butoxycarbonylamino-4-methoxyphenylglycine in Example 1 [4_ (2_morpholin-4-yl-2-oxo-ethoxyphenyl)-acetic acid, with the exception that 2-chloro-1 - phenanthyl-4-yl-ethanone is used instead of armor-free. HRMS ·· Observed mass of C31H32IN406+ (M+H+) ·· 683 1363 ; Calculated mass: 683.1613. Example 12 (2S,3S)-2-[4-(3-Fluoro-4-methoxy-phenyl)_2,5_ Bilateral oxy-imidazolium-1-yl]-'(4-iodo-phenyl)-3-phenyl-butanamine, isomer 丄

Prepared by the same method as described in Example 1, except that (1) 4-iodoaniline was used in place of 4-bromoaniline in step 2, and a third butoxycarbonylamino group was used in step 4. -[3-Fluoro-4-methoxy"phenyl]-acetic acid is substituted (with -2,2-butoxycarbonylamino-4-methoxyphenylglycine and (iu) will be 2 after step 5 The diastereomers were separated by cerium oxide chromatography using a methanol gradient elution between 〇.2 and ι.5% v/v in dichloromethane. The fractions containing the second eliminating component were separated. Collect and send to step 6. Prepare second butoxycarbonylamino-[3_fluoro-4-yloxy-phenyl]-B 128748.doc as described in w〇2〇〇6/〇29862 -42- 200848028 588.0790 ; tf HRMS : mass of observed mass: 588.0790. ) Example 13 - Bis-oxy-meridene isomer 2 (2S'3S)-2-[4-(3-fail-4 -methoxy-stupyl), dimethyl-1-yl]-indole-(4-iodo-phenyl)-3-phenyl-butanamine

The third method was followed by separation of the diastereomers as described in Example 12 after step 5, except that the HRMS was collected in the layer and sent to the lysing component in step 6: C26H24FIN304+ Observation quality (m+h+) Calculated mass: 588.0790. Example 14 588.0785 (2S,3S)-2-((R)-2,5-di- oxy-4-thiophene-3 (4-indole-styl)_3_phenyl-butanamine-port Rice mouth sitting

» But the exception is (R)-di-dibutoxy-carbylamino-p-phen-3-yl-acetic acid ^ ^ 驮 instead of (R) • oxy 1k-amino-4-yloxyphenyl Amino acid. 128748.doc -43- 200848028 HRMS : Observed mass of C23H21IN303S + (M+H+) : 546.0339 ; Calculated mass: 546.0343. Example 15 (S)-2-(2,5-Di-oxy-imidazolidin-1-ylfluoro-4-moth-phenyl)-3-p-tolyl-propionamide

Prepared by the same method as described in Example 1, except for (1) using (S)-2-t-butoxycarbonylamino-3_p-tolyl-propionic acid in step 1 (2S, 3S)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid, (ii) 2-fluoro-4-iodoaniline in place of 4-bromoaniline in step 2 and (iii) in step 4 Instead of (R)-t-butoxycarbonylamino-4-methoxyphenylglycine, a third butoxycarbonylamino-glycine is used. HRMS : Observed mass of C19H18FIN303 + (M+H+) : 482.0372 ; Calculated mass: 482.0372. Example 16 (S)-2-(2,5-Di-oxy-imidazolidin-1-ylfluoro-4-iodo-phenyl)-3-(4-fluoro-phenyl)-propanamide

128748.doc -44- 200848028 was prepared by the same method as described in Example 1, except that (1) (S)-2-t-butoxycarbonylamino-3-(4-) was used in Step 1. Fluoro-phenyl)-propionic acid instead of (2S,3S)-2-tert-butoxycarbonylamino-3-3-phenyl-butyric acid, (Η) 2-fluoro-4-iodoaniline used in step 2 Substituting 4-bromoaniline and (iii) replacing the (R)-t-butoxycarboxyamino-4-methoxyphenylglycine with a third butoxycarbonylamino-glycine in step 4. . HRMS : Observed mass of C18H15F2IN3〇3 + (M+H+) : 486.01 16 ; Calculated mass: 486.0121. Example 17 (S)-2-(2,5-di- oxo-methane-bite-1_Kidend-4-anthrace-phenyl)-3-o-indole phenyl-propanamide

Prepared by the same method as described in Example 1, except that (1) was replaced with (S)-2-t-butoxycarbonylamino-3-o-tolyl-propionic acid in step 1 (2S, 3S)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid, (ii) in step 2, 2-fluoro-4-money aniline is used in place of 4-isoaniline and (iii) is in step, In step 4, a third butoxycarbonylamino-glycine is used in place of (R)-t-butoxycarbonylamino-4-methoxyphenylglycine. HRMS : observed mass of C19H17FIN3Na03+ (M+Na+): 504.0190; Calculated mass: 504.0191. Example 18 128748.doc -45- 200848028 (S)-N-(2-fluorophenyl)-2-[(R)-4-(4-methoxy-phenyl&gt;2,5-di-side oxygen Base-imidazolidine-^ phenyl phenyl-propanamide

Prepared by the same method as described in Example 4 except that 2-fluoro-4-iodoaniline was used in place of 4-iodoaniline in Step 2. HRMS : Observed mass of C25H22FIN3 〇 / (M+H+) : 574.0629 ; Calculated mass: 574.0634. Example 19 (S)-2-[(R)-4-(4-ethoxy-phenyl)-2,5-di- oxy-miso sigma _1 _ base; Μ (2-fluoro- 4-iodo-phenyl)-3-phenyl-propanamide

Prepared by the same method as described in Example 1, except that (1) was replaced with (S)-2-second butoxygreen amino-3-phenyl-propionic acid in step 1 (2S, 3S)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid, (ii) 2-fluoro-4-iodoaniline in place of 4-bromoaniline in step 2 and (iii) in step 4 The (R)-t-butoxycarbonylamino-4-tetraethoxyphenylglycine was used in place of (R)-t-butoxycarbonylamino-4-methoxyphenylglycine. (R)-Tertibutoxycarbonylamino-4-ethoxyphenylglycine was prepared as described in Example 48, but the example 128748.doc-46·200848028 was replaced by ethyl iodide 2_(2_ Bromo-ethoxy group &gt; tetra-argon-pyran. HRMS: C26H23FIN3Na04+ observed mass (M+Na+): 610.0605; Calculated mass: 610.0609. Example 20 (S)-iV-(2_fluoro_4_iodo-phenyl)- 2-{(R)_4_[4-(2-hydroxy-ethoxy)-phenyl b 2,5-di-oxy-imidazolidin-1-yl-3-phenyl-propanamide

Prepared by the same method as described in Example 18 except that (R)-t-butoxycarbonylamino-{4-[2-(tetrahydro-pyran-2) was used in Step 4. -(yloxy)-ethoxy]-phenyl-acetic acid instead of (R)-t-butoxycarbonylamino-4-methoxyphenylglycine. HRMS : Observed mass of C26H24FIN305+ (M+H+): 604.0738 ; Calculated mass: 604.0739. Example 21 (S)-7V-(2H-A-phenyl)-2-{(indole-[4-(2-methoxy-ethoxy)-phenyl]-2,5-di-oxyl- Metformin-l-yl}-3-phenyl-propanamide

Prepared in a similar manner as described in Example 1, except that (1) in step 128748.doc-47-200848028, step 1 uses (S)-2-t-butoxycarbonylamino-3-phenyl- Propionic acid replaces (2S,3S)-2-t-butoxycarbonylamino-3-phenyl-butyric acid, (ii) in step 2, 2-fluoro-4-iodoaniline is used instead of 4-bromoaniline (iii) Substituting (R)-t-butoxycarbonylamino-[4-(methoxy-ethoxy)-phenyl]-acetic acid for the (R)-t-butoxycarbonyl group in step 4. Amino-[4-hydroxy-phenyl]-acetic acid. (R)-Tertibutoxycarbonylamino[4-(decyloxy-ethoxy)-benzyl]-acetic acid was prepared as described in Example 80. HRMS : Observed mass of C27H26FIN305+ (Μ+Η+) : 618.0896 ; Calculated quality: 618.0896. Example 22 (S)-2-{(r)-4_[4-(2-Ethoxy-ethoxyphenyl]-2,5. di-oxyl-scented sulphate-1-kib TV-( 2-fluoro-4-iodo-phenyl)-3-phenyl-propanamide

Prepared by the same method as described in Example 18 except that (R)-t-butoxycarbonylamino-[4-(2-ethoxy-ethoxy) was used in Step 4. _ Phenyl l-acetic acid instead of (R)-t-butoxycarbonylamino-4-methoxyphenylglycine. HRMS : observed mass of c28H27FIN3Na〇5+ (M+Na+): 654 〇 874 ; Calculated mass: 654.0871. Example 23 (S) #-(2-Motor-4-Moth-Phenyl)-2-((R)-4-{4-[2-(2-Pyly-ethoxy)·B 128748.doc -48 - 200848028 oxyl·styl}-2,5-di-oxy-imidazolium-fluorenyl-yl)-3-phenyl-propanamide

Prepared by the same method as described in Example 18 except that (R)-t-butoxycarbonylamino-(4_{2-[2_(tetrahydro-pyran-2) was used in step 4. -(yloxy)-ethoxy]-ethoxyphenyl)-acetic acid instead of (r)-t-butoxycarbonylamino-4-methoxyphenylglycine. HRMS : C28H27FIN3Na06+ observed mass (M+Na+): 670.0819 ; Calculated mass: 670,0821. Example 24 (8)-'^Fluorine-Phosin-Phenyl-"":"^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Imidazolidin-1-yl)_3_phenyl-propanamide

Prepared by the same method as described in Example 1, except that (S)-2-(3)-butoxycarbonylamino-3-phenyl-propionic acid was substituted in step 1 (2S) , 3S)-2-t-butoxy-Weiylamino-3-phenyl-butyric acid, (ϋ) in step 2 using 2-fluoro-4-iodoaniline instead of 4-bromoaniline and (iii) In step 4, (R)-t-butoxycarbonylamino-[4-(decyloxy-ethoxy-ethoxy)-phenyl]-acetic acid is used instead of (R)-t-butoxycarbonyl. Amino-[4-methoxy-phenyl]-B 128748.doc -49- 200848028 Preparation of (R)-Tertibutoxycarbonylamino-[4_(methoxy) as described in Example 48 Ethyloxy-ethoxy)-benzyl]-acetic acid, with the exception of using 1_(2_ _ ethoxy)-2- methoxy-ethane instead of 2-(2-bromo-ethoxy) _ tetrahydropyran. LC-MS : Observed mass of C29H3 〇FIN306+ (M+H+) : 662.13 ·, Calculated Mass: 662.12. Example 25 (S)-2-{(R)-4-[4-((R)-2,3-Dihydroxy-propoxy)-phenyl]_2,5-di-oxy-imidazole- 1-yl}-#-(2-fluoro-4-iodo-phenyl)-3-phenyl-propanamide

Prepared by the same method as described in Example 2 except that (1) 2-fluoro-4-iodoaniline was used instead of 4-bromo-2-fluoro-aniline and (ii) ((s)-2- Tributoxycarbonylamino-3-phenyl-propionic acid in place of (2S,3S)-2-t-butoxycarbonylamino-3-phenyl-butyric acid. HRMS : observed mass of C27H26FIN306+ (M+ H+): 634.0839; Calculated mass: 634.0845. Example 26 (S)-2-[(R)-4-(4-Ethylamino-phenyl)-2,5-di- oxy--scented squat _1-yl]-Ν-(2-fluoro-4-E-phenyl)-3-phenyl-propanamide

128748.doc -50- 200848028 was prepared by the same method as described in Example 29 except that (2R)-(4-acetamido-phenyl)-t-butoxycarbonylamino group was used. Acetic acid replaces (2R)_t-butoxycarbonylamino-(2,3-dichloro-benzo[μ]dioxol-6-yl: acetic acid. Prepared as follows (2RH4-acetamido-benzene (3) tert-butoxy-amino-acetic acid: (1) to (2R)-amino-phenyl-acetic acid (1 〇〇g, 66 2 mm 〇 1) in water (8) mL) Sodium hydroxide (2·65 g, 66 3 ) was added to the suspension. After stirring for 2 minutes, acetic anhydride (12·5 mL, 132 2 mm 〇1) was added and the mixture was stirred at ambient temperature for 15 minutes. Acidified to pH = 1 with hydrazine M aqueous hydrochloric acid and a colorless precipitate of (2 s)-acetamido-phenyl-acetic acid was collected by filtration and dried (10.24 g, 80%). LC-MS: C10H12NO3 + Observed mass: 194; calculated mass: 194. (2) Dissolve (2R)-acetamido-phenyl-acetic acid (97 g, 5〇5 ί mm〇1) in concentrated sulfuric acid at -10 °C (25 mL), and concentrated sulfuric acid (4.2 mL, 100 mmol) was added dropwise while stirring while maintaining the temperature. After stirring for 30 minutes under 1:1 Torr, the reaction mixture was poured onto EtOAc EtOAc (EtOAc). Amino-(4-nitro-phenyl)-acetic acid. LC-MS·· C10HllN2O5+ Observed mass: 239; Calculated mass: 194. (3) (2R)-Ethylamino group _(4•Nitro _Phenyl)-acetic acid (5 〇〇, 2 1 〇mmol) is dissolved in 2 Μ hydrochloric acid under reflux with a # ”^. ^ Fen, heated to l〇〇t in the night: lasts 3.5 hours. The reaction mixture was cooled to the surroundings, pruritus + door W, and the mixture was dried by freeze drying to dry half of the reaction mixture. The residue from the cold ling, _ _ _ / dried fruit was suspended in water (2 In mL) and with saturated aqueous sodium carbonate solution to obtain a solution of pH=l〇. 128748.doc -51 - 200848028 Add two chews (6 mL) to the aqueous mixture, followed by the addition of dicarbonate Tributyl ester (368 μί, 1.6 mmol) and the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was acidified with 20% w/v aqueous citric acid, followed by ethyl acetate The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification by dissolving afforded (2R)-tert-butoxycarbonylamino-(4-nitro-phenyl)-acetic acid (372 mg, &gt; 100%) as a colorless oil. LC-MS: Observed mass of C13H17N206+: 297. Calculated mass: 297. Add a small amount of 10% charcoal to a solution of (2R)-t-butoxycarbonylamino-(4-nitro-phenylacetic acid (35 mg, &lt;1.18 mmol) in absolute ethanol (15 mL) Palladium and the mixture was stirred under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through a pad of diatomaceous earth and the diatomaceous earth was dissolved in anhydrous ethanol. The filtrate was concentrated in vacuo and then purified by silica gel chromatography. (2R)-(4-Amino-phenyl)-tert-butoxycarbonylamino-acetic acid (146, 46%) was obtained as a yellow oil. 〇LC-MS: Observed mass: 267; Calculated mass: 267. (2RH4-Amino-phenyl)-t-butoxycarbonylamino-acetic acid (1 mg, 0.376 mmol) in dichloromethane Pyridine (36 pL, 0.45 mmol) and acetic anhydride (42, 〇 44 mm 〇 1) were added to the solution in (2 mL) and the mixture was stirred at ambient temperature for 2 hr. 1 Μ Μ </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> 8.doc-52-200848028 A gradient elution of methanol in di-methane to afford (2R)-(4-acetamido-phenyl-tert-butoxycarbonylamino-acetic acid as a yellow solid. 59 mg, 5 1 %) 〇LC-MS ·· C15H19N205· Observed mass: 307 ; Calculated mass ·· 307 LC-MS : Observed mass of C26H23FIN404+ (M+H+) : 601 ; Calculated mass · · 6 01. Example 27 (S)-7V-(2-Fluoro-4-iodo-phenyl)-2-{(R)-4-[4-(2•methoxy-acetamido)-phenyl]_2 , 5_di-oxy-imidazolium_ι_基卜3_phenyl-propanamide

Prepared by the same method as described in Example 1A, except that (1) 2-fluoro-4-iodoaniline was used in place of 4-bromoaniline in step 2, and (ii) hexafluorophosphoric acid was added in step 4. -benzotrien. Sodium-1_yl bis(tetradecyl) hydrazine is used as a coupling reagent instead of bismuth trifluorophosphate benzotriazole-tetramethyl hydrazine and (iii) is used in step 4 (R) _Tertibutoxycarbonylamino]['(2-methoxy-acetamido)-phenyl acetoacetate instead of (R)-t-butoxycarbonyl fe: phenyl-4-oxooxy -Glycine. (R)- was prepared by the same method as the preparation of (R)-(4-acetamido-phenyl)-t-butoxycarbonyl-amino-acetic acid as described in Example 26. Third butoxycarbonylamino-['(2-decyloxy-acetamido)-phenyl]-acetic acid', with the exception of the use of methoxy-ethyl hydrazine in step 5 instead of 128748.doc - 53- 200848028 Acetic anhydride LC-MS : Observed mass of C27H25FIN405 + (M+H+) : 63 1 ; Calculated mass: 631 〇Example 28 (S)-2-{(R)_4-[4-(2- Amidino-acetamido)-phenyl]-2,5-di-oxy-imidazole pyridine 基 基 # #-(2-fluoro-4-iodo-phenyl)-3-phenyl- Propylamine

Prepared by the same method as described in Example 1, except that (1) 2-fluoro-4-iodoaniline was used in place of 4-bromoaniline in step 2, and (ii) bismuth hexafluorophosphate was added in step 4. Benzotriazol-1-yl-TV, bis(tetramethylene)anthracene is used as a coupling reagent instead of hexafluorophosphoric acid (9-benzotriazol-1-yltetramethylguanidine and (iii) and in steps (4) using (R)-t-butoxycarbonylamino-[4-(2-dimethylamino-acetamido)-phenyl]-acetic acid instead of the third butoxycarbonylamino-4-methyl Oxyphenyl-glycine. Prepared by the same procedure as for the preparation of (R)-(4-acetamido-phenyl)-t-butoxycarbonyl-amino-acetic acid as described in Example 26 ( R)_Tertibutoxycarbonylamino 44-(2-dimethylamino-acetamido)-phenyl]-acetic acid, with the exception that 2-diamino-acetic acid gas is used in step 5. Substituting acetic anhydride LC-MS : Observed mass of C28H28FIN5〇4+ (M+H+) : 644 ; Calculated mass: 644 〇 Example 29 128748.doc -54- 200848028 (S)-2-[(R)-4- (2,3-Dihydro-benzo[Μ]dioxane_6_yl)_2,5-di-oxy--17 m sigma sigma-1 -yl]-#-(2-fluoro-4 -E-phenyl)-3-phenyl-propionamidine amine

Prepared by the same method as described in Example 18 except that (1) was replaced with (2S)-2-t-butoxycarbonylamino-3-phenyl-propionic acid in step 1 (2S, 3S)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid and (ii) using (2R)-t-butoxycarbonylamino-(2,3-dihydro) in step 4. -Benzo[palladium/didiohexan-6-yl)-acetic acid (prepared according to the procedure of Bohme, Ε·Η·W· et al., 乂 MW. C/zem. 79, 23, 405-412) Instead of (R)-t-butoxycarbonylamino-{4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl-acetic acid. HRMS : Observed mass of C26H22FIN3〇5 + (M+H+): 602.0587 ; Calculated mass: 602.0583. Example 30 (S)-l (2-Fluoro-4_iodo-phenyl)_2_[(]^_4_(4_methoxy-phenyl)_2,5_di-oxyl j-sialidine-1-yl] -3-p-tolyl-propanamide

The exception is (1) by the same method as described in Example 1, 128748.doc -55- 200848028 Step 1 using (S)-2-t-butoxycarbonylamino-3-3-p-tolyl - propionic acid replaces (2S,3S)-2-t-butoxycarbonylamino-3-phenyl-butyric acid and (ii) replaces 4-bromoaniline with 2-fluoro-4-iodoaniline in step 2. . HRMS : Observed mass of C26H23FIN3Na04+ (M+Na+) : 610.0613 ; Calculated mass: 610.0609. Example 31 (S) j-(2-Fluoro-4-iodo-phenyl)-3-(4-fluoro-phenyl)-2_[(R)-4-(4-methoxy-phenyl:)- 2,5_di-oxy-imidazole-1-yl]-propanamide

Prepared by the same method as described in Example 4, except that (1) (S)-2-(2)-butoxy-phenylamino- 3-(4-1-phenyl)- Propionic acid is substituted for (S)-2-t-butoxycarbonylamino-3-phenyl-propionic acid and (ii) 2-fluoro-4-iodoaniline is used in step 2 instead of 4-iodoaniline. HRMS : Observed mass of C25H21F2IN3〇4+ (M+H+): 592.0539 ; Calculated mass: 592.0540. Example 32 (S)-3-(4-Chloro-phenyl)-TV-(2-fluoroIiodophenyl)-2-[(R)-4-(4-decyloxy-phenyl)-2 , 5-di-oxy-imidazolidin-1-yl]-propanamide

128748.doc -56- 200848028 was prepared by the same method as described in Example 1, except that (1) (S)-2-di-dibutoxy-phenylamino-p-chloro-propionic acid was used in step 1. Instead of (2S,3S)-2-t-butoxycarbonylamino-3-phenyl-butyric acid and (丨丨), 2-fluoro-4-iodoaniline was used in place of 4-bromoaniline in step 2. HRMS · Observed mass of C25H2iC1FIN304+ (M+H+) ·· 608.0241 ; Calculated mass: 608.0244. Example 33 (S)-3-(4-Cyano-phenylfluoro-4-E-phenyl)-2-[(R)_4-(4-methoxy-benyl)-2,5-, One side milk-scented salivary-1 -yl]-propanol

Prepared by the same method as described in Example 1, except for (1) using (S)-2_t-butoxycarbonylamino-3-3-(4-cyano-phenyl)_ in step 1. Propionic acid replaces (2S,3S)-2-t-butoxycarbonylamino-3-phenyl-butyric acid and (ii) 2-fluoro-4-indan phenylamine is used in place of 4-bromoaniline in step 2. HRMS : Observed mass of C26H21FIN404+ (M+H+): 599.0575; Calculated mass: 599.0586. Example 34 (S)-TV-(2-Fluoro-4-iodo-phenyl)-3-(4-decyloxy-phenyl)-2-[(R)-4-(4-decyloxy- Phenyl)_2,5-di-oxy-imidazolidinyl-fluorenyl]-propanamide 128748.doc -57- 200848028

Prepared by the same method as described in Example 1, except that (1) (S)-2_T3, δ, methoxycarbonylamino-3-(4-methoxy) was used in step 1. -phenyl)-propionic acid instead of (2S,3S)_2_t-butoxyaminoamino-3-phenyl-butyric acid and (9) in step 2, 2-fluoro-4, aniline instead of 4-formanilide .

Calculated quality: 604.0739. Example 35 HRMS: C26H24 cis 3 〇, observed mass (_+): 6〇4 0739; count (8) also (214-brown phenyl (cardiomethoxy-phenyl)_2,5-di- oxy-imidazole Pyridin-1-yl]-3-(4-trifluoromethyl)phenylpyridinium

Prepared by the same method as described in Example 1, except that (1) (S)-2-t-butoxycarbonylamino-3-(4-trifluoromethyl-phenyl) was used in Step 1. - propionic acid replaces (2S,3S)-2-t-butoxycarbonylamino-3-phenyl-butyric acid and (ii) replaces 4-bromo-4-iodoaniline with 4-bromo-2-amine in step 2. aniline. HRMS: observed mass of C26H21F4IN304+ (M+H+): 642.0507; calculated mass 642.0508. Example 36 128748.doc -58- 200848028 (S)4(2-Fluoro-3-iodo-phenyl)-3-(3-fluoro-phenyl)-2-[(R)-4-(4-A Oxy-phenyl)_2,5-di- oxy-imidazolidinyl-1-yl]-propanamide

Prepared by the same method as described in Example 1, except that (1) (S)-2-t-butoxycarbonylamino-3-3-(fluoro-phenyl)-propyl was used in step 1. The acid replaces (2S,3S)_2-t-butoxycarbonylamino-3-phenyl-butyric acid and (ii) 2-fluoro-4-iodoaniline is used in place of 4-bromoaniline in step 2. HRMS : observed mass of C25H20F2IN3NaO4+ (M+Na+) : 614.0350 ; Calculated mass: 614.0359. Example 37 (S)-A^(2-Fluoro-4-iodophenyl)-2-[(R)-4-(4-methoxy-phenyl)-2,5-di-oxy-imidazole Pyridin-1-yl]_3_meta-phenyl-propanamide

Prepared by the same method as described in Example 1, except that (1) Substituting (S)-2 -Secondoxybutylamino-3-m-tolyl-propionic acid in step 1 (2S) , 3S)-2-t-butoxymethylamino-3-phenyl-butyric acid and (Π) used in step 2 instead of 4-bromoaniline in place of 4-bromoaniline. HRMS : Observed mass of C26H23FIN3Na04+ (M+Na+): 610.0607; 128748.doc -59- 200848028 Calculated mass: 610.0609. Example 38 (S)-7V-(2-Fluoro-4-iodo-phenyl)-2-[(R)-4-(4-decyloxy-phenyl)_2,5-di-oxy-imidazole Pyridin-1-yl]-3-o-phenylphenyl-propanamide

Prepared by the same method as described in Example 1, except for (1) using (S)-2-tert-butoxycarbonylamino o-phenyl-propionic acid in step 1 (2S, 3S) 2-tert-butoxycarbonylaminophenyl-butyric acid and (i) used 2-fluoro-4-iodoaniline in place of 4-bromoaniline in step 2. HRMS: observed mass of C26H24FIN3〇4+ (M +ir) : 588 〇7 calculation mass: 588.0790. Example 39 (8) Preparation (2_ gas-toothed moth, stupid, methoxy-phenyl)-2-, 4-(4-methoxy-phenyl) -2,5_di-oxyl-flavor. sit-n-yl]-propanamide

The procedure was carried out by the same procedure as used in the first step of Example 4 (S)-2, except for (1) in the butyloxycarbonylamino-3-(2-methoxy-phenyl-128748) .doc ~ 60 - 200848028 base)-propionic acid in place of (S)-2-t-butoxycarbonylamino-3-phenyl-propionic acid and (Π) 2-fluoro-4-iodine used in step 2 Aniline replaces 4-iodoaniline. HRMS : Observed mass of C26H24FIN305 + (M+H+) : 604.0745 ; Calculated mass: 604.0739. Example 40 (S)-7V-(2-Fluoro-4-iodo-phenyl)-2-{(R)-4-[4-(2-hydroxy-ethoxy)-phenyl]-2,5 - Bis-oxy-imidazolidin-1-yl}-3-(2-methoxy-phenyl)-propanamide

Prepared by the same method as described in Example 39, except that (1) (R)-t-butoxycarbonylamino group _{4_[2_(tetrahydro-pyran-2-yloxy) was used in step 4. Substituting ethoxyphenyl-acetic acid (prepared as described in Example 48) in place of (R) second butoxycarbonylaminomethoxyphenylglycine and (ii) as in Example 48 Go to step 6. , HRMS · c27H26FIN306+ observation quality (M+H+): 634 〇 842 ; calculation quality: 634.0845. Example 41 ^(2-Fluoro-4_indole-phenyl)_2_[(R)_4_(4-methoxy-phenyl di-oxy-mi-m-butyl group]_3_(2_trifluoromethyl) Phenyl)·propanamine, isomerism (1) 128748.doc -61 - 200848028

Prepared by the same method as described in Example 4 except that (1) used in step 1 (S)-2-t-butoxycarbonylamino-3-(2-tri-methyl-phenyl) - propionic acid instead of (S)-2-t-butoxycarbonylaminophenyl-propionic acid, (u) in step 2 using 2-1-4-carbon aniline instead of 4-indolyl aniline, (out) The (s)_2_f amino-#-(2-fluoro-4-iodo-phenyl)-3-(2-trifluoromethyl-phenyl)-propanamine trifluoroacetate is in step 3. Separating and using triethylamine and (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride as a coupling reagent instead of hexafluorophosphate/benzotriazole_1 In the case of _-tetramethyl hydrazine, it is used directly in step 4, and (iv) after performing step 5, 2_[(r)_2•amino-2_(4-decyloxy-phenyl)-B Diastereomer of guanidino]1_(2-fluoro-4-iodo-phenyl)-3-(2-trifluoroindolylphenyl)-propanamide (by racemization in step 2) The action was carried out by gelatin chromatography by 4 Å and 60% v/v of hexanes in hexanes. The slower moving components are collected and concentrated in a vacuum and sent to step 6. HRMS : C26H21F4IN3 (V-observed mass (M+H+): 642 〇5〇2 ; Calculated mass: 642.0508. Example 42 7V-(2-Fluoro-4-iodo-phenyl)_2-[(r)_4-( 4-methoxy-phenyl)_2,5-di-oxy-imidazolidine-1-yl]-3-(2-trifluoromethyl-phenyl) propylamine, isomer 2 128748. Doc -62- 200848028

The residue was prepared by the same method as described in Example 41, except that the collection was from the chromatographic-isolation 2 side 2•amine 2 —(cardioxy-phenyl)-ethylamine amine N (2) -Fluorine_4-iodo-phenyl)_3_(2·trifluoromethyl-phenylheptylamine

Ii. The faster moving component of the enantiomer and concentrated in vacuo and sent to 6 〇 HRMS · C26H20F4IN3NaO4+ observed mass (M+Na+): 664.0327; Calculated mass: 664.0327. Example 43 Fluoro-4-iodo-phenyl)-2-{(R)-4-[4-(2-hydroxy-ethoxy)- phenyl 2,5-di-oxy-imidazolidin-1- -3--naphthalen-2-yl-propanamide

〇

OH was prepared by the same method as described in Example 48 except that (i) the following steps were carried out to replace steps 1-3 described in Example 48 and (ii) in step 4 The bismuth hexafluorophosphate-benzotriazol-1-yl-branched from #-bis(tetradecyl) hydrazine was used as a coupling reagent in place of the fluorenyl benzotriazin-1-yltetradecyl fluorenyl hexafluorophosphate.

Step 1: At 0 ° C, under a dry nitrogen atmosphere, '荞A 128748.doc •63-200848028 methoxycarbonylamino)-3-naphthalen-2-yl-propionic acid (1.〇g, 2.3 0 mm〇1) and 2,fluoro-4-iodoaniline (434 mg, 1.84 mmol), triphenylphosphine (〇·94 g, 3.45 mmol) and pyridine (〇·3 9 mL, 4 6〇mm〇1 N-bromobutaneimine (〇·61 mg, 3 45 mmol) was added in two portions in dichloromethane (1 〇 〇). The mixture was stirred under 2 hours. The reaction mixture was purified by silica gel chromatography over a 30-minute gradient elution from 1% to dichloromethane to 1% methanol to 9% dioxane. Concentration of the product-containing fractions gave [(S)-l_(2-fluoro-4-iodo-phenylaminecarbamimidyl) 2 -naphthyl-ethyl]-carbamic acid 977 as a yellow solid. -苐-9-基甲g (105 g, 70%). LC_MS : C34H27FIN203 + observed mass (M+H+): 657 ; calculated mass: 657. Step 2: To [(S)-l-(2-fluoro-4-iodo-phenylamine-mercapto)_2_naphthalen-2-yl-ethyl]-carbamic acid 9//· -9- Piperidine (6 mL) was added to a solution of methyl ester (1·05 g, i 6 〇 〇 1) in dichloromethane (24 mL) and the mixture was stirred at room temperature for 1 hour. After removal of the solvent, the residue was purified by silica gel chromatography eluting from 100% hexanes to 40% ethyl acetate / 6% hexanes over 30 min. The product-containing fraction was concentrated to give (s)-2-amino-1-(2-fluoro-4-iodo-phenyl)-3-naphthalen-2-yl-propanamine (39 呈) as a yellow solid. Mg, 56%) 〇LC-MS : observed mass of C19H17FIN2〇+ (Μ+Η+) : 435 ; calculated mass: 435 . LC-MS : Observed mass of C3〇H26FIN305 + (Μ+Η+) : 654 ; Calculated mass: 654 . Example 44 128748.doc -64- 200848028 (2S,3S)-2_((R)-2,5-di-sideoxyl phenyl-imidazolidin-1-yl)-, (2-fluoro-4-iodine) -phenyl)-3-phenyl-butanamine

Prepared by the same method as described in Example 1, except that (1) 2-fluoro-4-iodoaniline was used in place of 4-bromobenzamine in step 2 and (R)- was used in step 4. The third butoxymethylaminophenyl acetate is substituted for (r)-t-butoxycarbonylamino[4-methoxy-phenyl]-acetic acid. HRMS : C25H21FIN3Na (visible mass of V (M+Na+): 580.0492; calculated mass: 580.0504. Example 45 (2S,3S)-7V-(2-fluoro-4-indole-phenyl)-2-[(R) -4-(4-methoxy-phenyl)_2,5-di- oxy-imidazolidine-1-yl]-3-phenyl-butanamine

It was prepared by the same method as described in Example 1, except that in the second step, 2-fluoro-4-iso, aniline was used instead of *-aniline. HRMS : Observed mass of C26H24FIN3〇4+ (m+h+): 588.0791 ; Calculated mass · · 588.0790. Example 46 128748.doc -65- 200848028 (2S,3S)-2-[(R)-4-(4-ethoxy-phenyl)-2,5-di-oxy--methane sigma] -iV-(2-fluoro-4-moth-phenyl)-3-phenyl-butylamine

Prepared by the same method as described in Example 44 except that (R)-t-butoxycarbonylamino-(4-ethoxy-phenyl)-acetic acid deuterated (step) was used in step 4. R)-di-dibutyl-based ylamino-phenyl-acetic acid. Preparation of (R)-Tertibutoxycarbonylamino group as described in Example 4, Step 4, for the preparation of (R)-t-butoxycarbonylamino-(4-methoxy-phenyl)-acetic acid _(4_Ethoxy-phenyl)-acetic acid' except that ethyl iodide was used instead of iododecane. HRMS : Observed mass of C27H26FIN304+ (M+H+) : 6〇2 〇 944 ; Calculated mass: 602.0947. Example 47 Bis-oxy-mi (2S,3S)-2-[(R)_4-(4-cyclopropylmethoxy-phenyl)_2,5-di-sit-butyl]-(2_qi _4_iodine_phenyl)_3·phenyl-butanamine

Prepared by the same method as described in Example 46, except that the (R)-t-butoxycarbonylaminol (R)-j-butyl carbonylamino group _(4) was used in Example 46. _cyclopropylmethoxy-phenyl>acetic acid for acetic acid

I28748.doc -66- 200848028 phenyl-phenyl)-acetic acid, with the exception of the use of bromodecylcyclopropane in place of ethyl. HRMS : observed mass of C29H28FIN3〇4+ (M+h+): 628.1094; calculated mass: 628.1 103. Example 48 (2S,3S)-iV_(2-fluoro-4-moth-phenyl)-2-{(R)-4-[4-(2-trans)-ethoxy)-phenyl]-2 , 5-tertiary oxy-imidazolidin-1-yl-p-phenyl-butanamine

Prepared by the same method as described in Example 1, except that (1) 2-fur-4-aniline was used instead of 4-bromoaniline in step 2, (ii) (R)- Tributoxycarbonylamino-{4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-acetic acid (prepared as described below) is substituted for (R)- Tributoxycarbonylamino-4-yloxyphenylglycine and (丨^) are carried out as described in the following step 6 to prepare (R)-dibutyloxycarbylaminotetrazole-pyran 2-(Alkyloxy)-ethoxy]-phenyl}-acetic acid: (R)-t-butoxycarbonylamino-(4-pyridyl-phenyl)-acetic acid (2·67 g, 10 Methyl) (Salituro, GM.; Townsend, CA. J. c/zem. Soc. 1990, &quot; 2, 760_770) was dissolved in W-dimethylformamide (70 mL) in an ice bath. Hydrogenated sodium (0·88 g, 60% in mineral oil, 22 mm〇l) was added in small portions. The mixture was allowed to warm to l ° ° C for 1 hour. 2-(2-Bromo-ethoxy)·tetrahydropyranium·7 m〇i, 11 mm〇l) was added dropwise to dimethyl decylamine (2 mL). The reaction 128748.doc -67- 200848028 mixture was stirred for 24 hours and then diluted with ice/water. The mixture was extracted with ethyl acetate. The aqueous layer was cooled in an ice bath and acidified using 丨·5 Μ potassium hydrogen sulfate aqueous solution to ρ Η = 2-3. The mixture was extracted with EtOAc (5×), EtOAc (EtOAc) Filter and evaporate the solvent to give (r)-t-butoxycarbonylamino-{4-[2-(tetrahydropyran-2-yloxy)-ethoxy]-phenyl as a solid white foam. Acetic acid (32 g, 82%) 〇 Step 6: at -40 ° C for 5 minutes to diphosgene (21.1 pL, 0,1 73 mmol) in 1:1 v/v toluene/tetrahydrofuran Add (28,3 8)-2-{(11)-2-amino-2-[4-(2-trans-ethoxy-phenyl)-phenyl]-ethyl to solution (2 mL total) N-(2-fluoro-4-E-phenyl)-3-phenyl-butanamine (180 mg, 0.289 mmol) with N,N-diisopropylethylamine (154 pL, 0.867 mmol) The mixture was washed with anhydrous dichloromethane (40 mL) and the residue was washed with a small portion of anhydrous dichloromethane. After 20 minutes at -40 ° C, the temperature was raised to -20 ° C for a further 15 minutes to complete the reaction. The colorless solution was diluted with ethyl acetate (100 mL) and successively washed with EtOAc EtOAc EtOAc (EtOAc) The aqueous layer was back extracted with ethyl acetate (2×50 mL). The combined ethyl acetate extract was diluted with an equal volume of dichloromethane and passed through a column of sodium sulfate located at the top of a 4" flash hose column. The solution was concentrated to afford a pale yellow residue (177 mg). The product was wet-milled with dichloromethane (5 x 2 mL) and the combined organic solution was chromatographed with 1% grading from 100% dioxane to 3% by silica gel (inactivated with methanol before use). Purification of the sterol/97% dioxane gradient elution. Concentration of the product containing fractions gave a glassy residue (98 128 748.doc * 68 - 200848028 mg). The residue was dissolved in a small volume of dichloromethane. The mixture was diluted with EtOAc (3 mL). Fluoroquinone-phenyl)_2_{(8)_heart [4_(2_carbyl-ethoxy)phenyl]-2,5-di-oxy-imidazolidinyl-pyridyl 3-phenyl-butanamine (Mat. .29 minutes, observed mass of C27H25FIN3Na05+ (M+Na+), 640 ; calculated mass, 640. lU NMR (DMSO-d6? 300 MHz) δΗ 10.11 (s? 1Η), 8.53 (s5 1H), 5·02 (d , J = 11.8 Hz, 1H) ppm (characteristic resonance). Example 49 (2S, 3S)-A^-(2-fluoro-4-E-phenyl)_2-{(S)-4-[4-( 2-yl-ethoxy)-phenyl]-2,5-di-oxy-imidazolidin-1-yl}_3_phenylbutanamine

(2S,3S)-TV-(2-Fluoro-4-iodo-phenyl)-2-{(R)-4-[4-(2-hydroxy-ethoxy)-phenyl]-2, A solution of 5-di-oxy-miso 11-but-1-yl}-3-phenyl-butylamine (prepared as described in Example 48) (50 mg, 0.081 mmol) was dissolved in methanol (3 mL) And stirred at ambient temperature for 4 days. The resulting mixture of isomers 128748.doc -69-200848028 was concentrated in vacuo and then subjected to supercritical fluid chromatography using Chiracel OJ column to pass 35% v/v at 100 bar and 3 cc. The carbon monoxide dissolution of the ethanol in acetonitrile was purified by dissolving in 2 ml per minute. The first dissolved compound is collected and concentrated in vacuo to obtain (28,38)_7^(2_fluoro_4_iodo-phenyl)-2-{(S)-4-[4-(2-hydroxy-B Oxylate &gt; Phenyl 2,5•di-oxy-imidazolidin-1-yl-3-phenyl-butanamine (9 mg, 18%). The second dissolving compound is equivalent to (2S, 3S) )-A/»(2-Fluoro-4-iodo-phenyl)-2-{(R)-4-[4-(2-hydroxy-ethoxy). stupid]. Sodium sulphate-^-based phenyl-butanamine (19·9 mg, 40%) LC-MS (reverse phase HPLC, C18 column, water/acetonitrile gradient)·· Rt=2 34 min, C27H25FIN3Na05+ Mass of observation (M+Na+), 640; calculated mass, 640. NMR (DMSO-d6? 300 MHz) δΗ 10.18 (s? 1Η)? 8.57 (s, 1Η), 4.84 (s, 1Η) ppm ( Characteristic resonance). Example 50 (2S,3S)_7V-(2-Fluoro-4-indolyl)-2-{(R)-4-[4-(2-decyloxy-ethoxy)- Phenyl]_2,5_di-oxyl- miso bite_ 1 _yl}_3-phenyl-butanamine

Prepared by the same method as described in Example 1, except that (1) 2-fluoro-4-indan phenylamine was used in place of 4-bromoaniline in step 2 and (丨丨) was used in step 4 (R) _Tertibutoxycarbonylamino-[4-(2-methoxy-ethoxy)-benzene 128748.doc -70- 200848028 base]-acetic acid substitution (R)-third butan gas g, , 虱Lithosylamino-[4-methoxy-phenyl]-acetic acid. Methoxy·ethoxy)-phenyl]^ was prepared as described in Example 80. )^基Μ胺基仰_

HRMS · C28H28FIN305 + Calculated mass: 632.052. The observed mass of Example 51 (Μ+Η+) • 632.1053;

Prepared in a manner similar to that described in Example 1, except that (1) 2-fluoro-4-iodoaniline was used instead of 4-bromoaniline in step 2 and (π) was used in step 4 (R)-second Oxycarbonylamino-[4-(2-ethoxy-ethoxy)-phenyl-acetic acid instead of (R)-t-butoxycarbonylamino-[4-methoxy-phenyl]_ Acetic acid. (R)-Tertibutoxycarbonylamino-[4-(2-ethoxy-ethoxy)-phenyl]-acetic acid was prepared as described in Example 48, except that 丨-bromo-2_ was used. Ethoxyethane replaces 2-(2-bromo-ethoxy)-tetrahydropyran. HRMS: Observed mass of C29H30FIN3O5 + (M+H+): 646.1 192; calculated mass · · 646.1209. Example 52 (2S,3 S)-7V»(2-Fluoro-4-iron-phenyl)-2 - {(R)-4-[4-(3-]-yl-propoxy)phenyl] -2,5-di-oxy-imidazolidine-1-yl}-3-phenyl-butanamine 128748.doc -71 - 200848028

Prepared by the same method as described in Example 48 except that (R)-di-dibutoxyaminoamino-{4-[3-(tetrahydro-l-butan-2-yloxy) was used. )-propoxyl l stupylacetic acid instead of (R)-tert-butoxycarbonylamino _ 丨 4_[2-(tetra 5L σ-Chen-2-yloxy)-ethoxy]-benzene Acetic acid. Preparation of (R)-t-butoxycarbonylamino-{4-[3-(tetrahydro-pyran-2-yloxy)-propoxy]-phenyl-acetic acid as described in Example μ The exception is the use of 2-(3-bromo-propoxy)-tetrahydropyran instead of 2-(2-bromo-ethoxy)-tetrahydropyran. HRMS : C28H28FIN305+ observed mass (M+H+): 632.1055 ; Calculated mass: 632.052. Example 53 (2S,3S)-7V-(2-Fluoro-4-bromo-phenyl)-2-{(R)-4-[4-(4-yl-butoxy)-phenyl]- 2,5_di-oxy-imidazolidin-1-yl-3-phenyl-butanamine

Prepared by the same method as described in Example 48 except for the use of (R)-t-butoxycarbonylamino-{4-[4-(tetrahydro- ethanoyloxy)-butoxy Substituted phenylacetic acid for the substitution of (R)-t-butoxycarbonylamino-{4_[2•(tetrahydro-n-butyl-2-yloxy)-ethoxy]-phenylacetic acid. Preparation of (R)-Tertibutoxycarbendyl [4_(tetrahydrooxy)butoxy]-phenyl}acetic acid as described in Example 48, 128748.doc -72-200848028, with the exception of 2_(4-Butyloxy)-tetrahydropyran was used instead of 2-(2-bromo-ethoxy)-tetrahydropyran. HRMS : observed mass of C29H3 〇FIN3〇5+ (μ+η+) : Μ6 12〇8 ; Calculated mass: 646.1209. Example 54 (2S,3SHH2-Fluoro-4-indole-phenyl)_2_((Ιι)_4·{4_[2_(2_yl-ethoxy)-ethoxy]-phenyl}-2,5- Bilateral oxy-mi. sitbit small base) _3_phenyl-butanamine

Prepared by the same method as described in Example 48 except that (R)·T-butoxycarbonylamino-(4_{2_[2_(tetrahydro-pyran-2-yloxy) Oxy]-ethoxy phenyl)-acetic acid instead of (R)-t-butoxycarbonylamine 'yl-{4_[2-(tetrahydro-piperidin-2-yloxy)-ethoxy • Phenyl}-acetic acid. Preparation of (R)-Tertibutoxycarbonylamino-[(4-{2_[2_(tetrahydro-guan-2-yloxy)-B) as described in Example 48 Oxy]-ethoxyphenyl)-acetic acid, with the exception of using 2-[2-(2·chloro-ethoxy yethoxy)-tetrahydro-pyran instead of 2·(2_bromo- Ethoxy)-tetrahydropyran. HRMS : observed mass of C29H30FIN3〇6+ (Μ+Η) : 662 1158 ·calculated mass: 662.1 158. Example 55 128748.doc -73 - 200848028 (2S'3S)K2- |^4'_phenyl)士((R)_4-{4_[2-(2-methoxyethoxy)-ethoxy]-phenyl b 2,5-di-oxy-imidazole -1-yl)-3-phenyl-butanamine soil _

Prepared by the same method as described in Example 1, except that (1) in step 2, 2 was used to replace 4·bromoaniline and (ii) was used in step 4 (R)-second. Butoxymethylamino-[4_(2♦methoxy-ethoxyethoxy)-phenyl]-acetic acid instead of (R) alkoxyamino-yl-methoxy- Phenyl]•acetic acid. (R)j tributoxyaminoamino-[4-(2-{2-methoxyethoxyphenyl)-phenylacetic acid was prepared as described in Example 48, with the exception of use 1·{2-/odor-ethoxy)-2_methoxy-ethane replaces 2_{2_bromo-ethoxy)-tetrahydro σ melon. HRMS : Observation of C30H32FIN3〇6+ f t(M+H+) ·(d) 13〇6 ; Calculated mass: 676.13 15. Example 56 (2S,3S)-2-{(R)-4-[4-((r)_2,3-Dihydroxy-propoxy)-phenyl]-2,5-di-oxy-imidazole Acridine-l-yl}oxime (2-fluoro-4-E-phenyl)-3-phenyl-butanamine

128748.doc -74- 200848028 was prepared by the same procedure as described in Example 114 except that 2-fluoro-4-iodoaniline was used instead of 2-chloro-4-iodoaniline in Step 2. HRMS : Observed mass of C28H28FIN3〇6+ (M+H+): 648.0995; Calculated mass: 648.1002. LC-MS (reverse phase HPLC, C18 tube enthalpy, water / acetonitrile gradient)·· Rt=3.55 min, C28H28FIN30, observed mass (M+H+), 648 ; calculated mass, 648 ° lU NMR (DMSO-d6) 300 MHz) δΗ 10.11 (s, 1Η), 8.52 (s5 1H), 5.02 (d, J=11.5 Hz, 1H) ppm (characteristic resonance). Example 57 (28,38)_2-{(8)-4-[4-((11)-2,3-Dihydroxy-propoxy)-phenyl]_2,5-di-oxy-imidazole -1-yl}-#-(2-fluoro-4-iodo-phenyl)-3-phenyl-butanamine

(2S,3S)-2](R)-4_[4-((R)-2,3-dihydroxy-propoxy)-phenyl]-2,5-di-oxy-imidazole _丨_Kibuyi (2_Fluoro-4_iodo-phenylphenyl-butanamine (prepared as described in Example 56) 〇6〇mg, 〇·25 mm〇i) dissolved in methanol (1G ml) It was allowed to stir at ambient temperature for 48 hours, then warmed to 50 C for another 6 hours. Purification by vacuum separation by supercritical chromatography using Chiracei containing 35% methanol in acetonitrile. The second fence was removed, and the solvent was removed in a vacuum and then the residue was applied to a Chiracel OD column to dissolve the carbon oxide at 10 Torr and 3 〇〇c 35/ί> methanol to dissolve at 2 ml per minute. The compound was collected and concentrated in vacuo to afford (2S,3S)-2-{(S)_4-[4-((R)-2,3-dihydroxy-propyl as a colorless solid. Oxy)-phenyl]-2,5-di-oxy-imidazolidin-1-ylfluoro-4-iodo-phenyl)-3-phenyl-butanamine (35 mg, 44%). The first dissolving compound is equivalent to (28,3 8)-2-{()-4-[4-((&amp;)-2,3-di-propyl-propoxy)-phenyl]-2, 5-terbi-oxy-imidazolidin-1-ylfluoro-4-iodo-phenyl)-3-phenyl-butanamine. HRMS ·· C28H28FIN306+ observation quality (M+H+): 648.0995 ; Calculated quality: 648.1002.

LC-MS (reverse phase HPLC, C18 column, water / acetonitrile gradient): Rt = 3.13 min, observed mass of C28H28FIN306+ (M+H+), 648; calculated mass, 648 〇4 NMR (DMSO_d6,300 ΜΗζ) δΗ 10.18 (s, 1H), 8.57 (s, 1Η), 4.84 (s, 1Η) ppm (characteristic resonance). Example 58 (23,3 8)-&gt;^(2-Fluoro-4-iodo-phenyl)-2-{(1〇-4-[4-(2-hydroxy-1-hydroxymethyl-ethoxy) Base)-phenyl]-2,5-di-oxy-imidazolidin-1-yl}-3_phenyl-butanamine

〇 \ OH OH was prepared by the same method as described in Example 1, except that (1) 2-fluoro-4-aniline was used instead of 4-bromoaniline in Step 2, and (Π) was used in Step 4 ( R)-Tertibutoxycarbonylamino][4-(2-hydroxy-po-hydroxymethyl-ethoxy)-phenyl]-acetic acid (prepared as described in Example 160) is substituted for (R)- Tributoxycarbonylamino-(4-decyloxy-phenyl)-acetic acid, (iii) before proceeding to step 6 128748.doc •76- 200848028 will be contained in (2S,3S)-2-{(R )-2-amino-2-[4-(2-trans-l_methyl-ethoxy)-phenyl]-acetamido}-#-(2-fluoro-4-iodo- The diol functional group in phenyl)_3_phenyl-butanamine is temporarily protected as bis-trimethylsulfenyl ether (as described in Example 丨丨4) and (iv) purified in step 6. And isolated (2S,3S)·沁(2_fluoro_4_moth·phenyl)-2-{(R)-4-[4-(2-hydroxy-i-hydroxyindole-ethoxy)-benzene (2S,3S)-2-{(R)-2, as previously described in Example 114, as described in Example 114, methylene-2,5-di-oxy-imidazolidin-1-yl-3-phenyl-butanamine 5-tertiary oxy-4-[4-(2-trimethylglyoximeoxy-1-trimethylsulfonyloxymethyl-ethoxy)_ Yl] - imidazole

Acid-catalyzed hydrolysis of nitrile-1-ylbubu-(2-fluoro-4-mothene-phenyl)-3-phenyl-butanamine. HRMS · Observational mass of C28H28FIN306+ (M+H+): 648.0991; nasal mass ΐ · 648.1002. Example 59 (28,3 8)-7^-(2-Fluoro-4_ moth-phenyl)-2-{(R)-4-[4-(3-methyl-oxetan-3-yl) Methoxy)-phenyl]-2,5-di-oxy-imidazolidin-1-yl}-3-phenyl-butanamine

Prepared by the same method as described in Example 48 except that (R)-t-butoxycarbonylamino-[4-(3-indolyl-oxetanyloxy)-- Phenyl]-acetic acid replaces (R)-t-butoxycarbonylamino group _{4·[2_(tetraqi_tram-2-yloxy)-ethoxyphenyl}-acetic acid. 128748.doc -77-200848028 prepared as described in Example 48, (R)-t-butoxycarbonylamino-[4-(3-methyl-oxetan-3-ylmethoxy)- Phenyl]-acetic acid, with the exception that 3-bromomethyl-3-methyl-oxo-succinimide was used in place of 2-(2-di-ethoxy)-tetrahydro britylene. HRMS : Observed mass of C30H30FIN3O5+ (M+H+) : 658 12〇2 ; Calculated mass: 658.1209. Example 60 f (2R,3S)_iV-(2-Fluoro-4-iodo-phenyl)-2-[(R)-4-(4-methylaminecarboxymethoxy-phenyl)-2 , 5-di-oxy-imidazole pyridine-fluorenyl]_3_phenyl-butanamine

Prepared by the same method as described in Example 48 except that (R)-second butoxycarbonylamino-(4-methylamine-methyl-methoxy-phenyl)-ethyl hydrazine #代(R)-苐Dibutoxyaminoamino_{4_[2_(tetrahydro-p-anranyloxy)-ethoxy]-stupylacetic acid. (R)-Tertibutoxycarbonylamino-(4-mercaptocarbamoylmethoxy-phenyl)-acetic acid was prepared as described in Example 48, except that 2-chloro-indolemethyl was used. _Acetylamine replaces 2_(2_bromo-ethoxy)·tetrahydrofuran. HRMS · C28H26FIN4Na (visible mass of V (M+Na+): 667 〇82〇; calculated mass: 667.0824. Example 61 (2S'3S)_2-{(R)-2,5·: sideoxy_4_[4_ (2_Sideoxy_2_σpyrrolidyl-ethoxy)-phenyl]L-small base b (2 gas 1 _phenyl) small stupid 128748.doc -78- 200848028 ketobutylamine

Prepared by the same method as described in Example 48 except that (R)-second butoxycarbonylamino group side oxy-2_πpyrrolidino-yl-yloxy)-phenyl group was used. ••Acetic acid replaces (R)_t-butoxycarbonylamino group_{4_[2_(tetrahydro-pyran-2-yloxy)-ethoxy]-phenylacetic acid. The (R)-t-butoxycarbonylamino group is prepared by a method similar to the method used for the preparation of (R)-t-butoxycarbonylamino-4-yl-methoxyphenylglycine. [4_(2_Phenoxy-2-indolyl-1-yl-ethoxy)-phenyl]-acetic acid, with the exception of 2-chloro-1 -pyrrolidin-1-yl-ethanone instead of moth Decane. LC-MS: C31H31FIN4 〇5+ spectroscopy J mass (M+H+): 685/687 · Calculated mass: 685/687. Example 62 (2S,3S)-2-[(R)-4-(4_{[bis-(2-carbyl-ethyl)-aminocarbamoyl]-methoxyphenyl)-2,5 _Two-side oxy-imidazolidin-1-yl]-, (2-fluoro-'iodo-phenyl)-3-phenyl-butanamine

Prepared by the same method as described in Example 48 except that 128748.doc -79-200848028 (11)-[4-(2-{bis-[2-(t-butylmethyl-decyloxy)) was used. Ethyl]-amino}-ethoxycarbonyl)-phenyl]-tert-butoxycarbonylamino-acetic acid instead of (R)-t-butoxycarbonylamino-{4-[2-(four Hydrogen-methane-2-yloxy)-ethoxy]-phenyl}-acetic acid. As in Example 48, the household is described as a preparation (R)-[4_(2-{double-[2-(third Butyl-dimethyl-decyloxy)-ethyl]-aminophenylethyloxy)-phenyl]-tert-butoxycarbonylamino-acetic acid, with the exception of using N,N-double- [2彳T-butyl-dimethyl-decyloxy)-ethyl]-2-chloro-acetamide was substituted for 2-(2-bromo-ethoxy)-tetrachloro britylene. HRMS ·· C31H32FIN4Na07+ observation quality (M+Na+): 741.1194 ; Calculated mass: 741.1192. Example 63 (4-{(R)-l-[(ls,2S)-l-(2-Fluoro-4-iodo-phenylaminemethanyl)-2-phenyl-propyl]-2,5 - Bis-oxy-mi-indoles of α-1,4-yl}-phenoxymethyl)-phosphonate

Prepared by the same method as described in Example 48 except that (R)-t-butoxycarbonylamino-[4-(dimethoxyphosphonylmethoxy)-phenyl was used. l. Acetic acid replaces (R)-t-butoxycarbonylamino group {4_[2_(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl-acetic acid. (R)-Tertibutoxycarbonylamino-[4.(dimethoxy-phosphonium methoxy)-phenyl]-acetic acid is prepared as follows: (1) Didecyl sulphate ( 2.0 g ' 18.2 mmol), trioxane (574 mg, 19.1 mm 〇l) and triethylamine (0·25 mL, ι·8 mmol) combined and heated 128748.doc -80-200848028 to 70 °C to be transparent Solution. After 1 h, the reaction was cooled and concentrated in vacuo overnight to afford crude dimethyl <RTI ID=0.0> (2) Add pyridine (1.4 mL, 16·7 mmol) to a solution of dimethyl hydroxymethyl-phosphonate (2.0 g, 14.5 mm Ql) in anhydrous di-methane (50 mL) at -20 °C. ), followed by the addition of trifluoromethanesulfonic anhydride (27 mL, 15 9 mmol). After mixing for 0.5 hours at 〇 C, the mixture was filtered through celite with a thin layer of silica gel. The filtrate was washed with aq. EtOAc (aq. EtOAc) EtOAc. The solvent was removed to give trifluoro-methyllithofyrphate dimethoxy-dishyl methyl ester as an oil (2. g, 53%) 〇 (3) sodium hydride (18.9 mg, 0·) (R)-Tertibutoxycarbonylamino-(4-based-bensyl)-acetic acid (100 mg) in an ice bath added to anhydrous dimethyl decylamine (2.5 mL) , 0.37 mmol). The mixture was allowed to warm to room temperature then trifluoro-methanesulfonic acid dimethoxy-phosphonium decyl ester (122 mg, 0.45 mmol). Stirring was continued overnight at room temperature. The reaction was poured into aq. EtOAc (1 mL) andEtOAc. The combined extracts were washed with aq. Evaporation of the solvent gave the tributyloxycarbonylamino (dimethoxy-phosphonylmethoxy)-phenyl]-acetic acid (12 mg, 83% yield). HRMS : Observed mass of C28H29FIN307P+ (M+H+): 696 〇766 ; Calculated mass · 696.0767. Example 64 (4-{(R)-l-[(lS,2S)-l-(2-fluoro-4-iodo-phenylaminemethanyl)_2-phenyl-propanyl 128748.doc -81 - 200848028 -2,5-di-oxy-imidazolidin-4-yl}-phenoxymethyl)-phosphonic acid

Add bromotrimethylnonane (〇·12 mL, 0.88 mmol) to (4-{(R)-l-[(lS,2S)-l-(2-fluoro-4·iodo-benzene) at room temperature Alkyl fluorenyl) 2-phenyl-propyl]-2,5-di-oxy--saltidine-4-yl}-phenoxymethyl)-phosphonic acid dimethyl hydrazine Prepared as described in Example 63 (79 mg, 0.11 mmol) in dichloromethane (2.0 mL). After 4 hours the reaction was concentrated in vacuo and diluted with water (5 mL). The precipitated solid was filtered and dried to give ^(^)-^[(1S,2S)-1-(2-fluoro-4_iodo-phenylaminemethanyl)-2-phenyl-propyl]_2, 5-di- oxy-imidazo-4-yl}-phenoxymethyl)-phosphonic acid (5 1 mg, 68%). HRMS : Observed mass of C26H25FIN307P+ (M+H+) ·· 668 〇453 ; Calculated mass · · 668.0454. Example 65 (2S,3S)|(2-Fluoro-4-iodo-phenyl)_2-((RM_isopropyl-2,5·di-oxy-saltyl-1-yl)_3_phenyl -butylamine

The fineness is the same as that described in Example 48, W-2-third oxygen county / ^ ' except for the use of methyl-butyric acid instead of (R) · third butoxide 128748.doc • 82- 200848028 Alkylcarbonylamino-{4-[2-(tetrahydro-piperidin-2-yloxy)-ethoxy]-phenyl}-acetic acid. HRMS : observation quality of CnHwFINsCV (Μ+Η+) · 524 〇84〇; calculation quality: 524.0841. Example 66 (2S,3S)-2-[4-(4-Cyclopropyl-phenyl)_2,5-dioxaoxy-oxazolidinyl]-iV-(2-fluoro-4-iodo- Phenyl)·3_phenyl_butanamine, isomer 1

~ Fine was prepared by the same method as described in Example 48, except for the use of the first, butoxymethylamino-(4. cyclopropyl-phenyl)-acetic acid instead of the third butoxycarbonylamine. Base-{4-[2_(slightly-pyran-2-yloxy)-ethoxy]phenyl-acetic acid. The third butoxymethylamine propyl-phenyl)-acetic acid system was prepared as follows:

Friends (1) will dissolve cyclopropyl benzoate (840 mg, 5.68 mm 〇1) in anhydrous dichlorocarbyl (2. 5 mL) and trimethyl sulfonate (756 mg, 7.394 〇 1) And 5 moths of the crystal in the king, and heated to the thief for i5 minutes. The reaction mixture was then concentrated in vacuo. () The concentrated orange solution from (1) was treated with 7 N ammonia in methanol (7 1, 2.22 mm 〇 1) and at machine T, under argon at a sealed tube for 2 〇 h. The solution was concentrated to a yellow residue (1.08 g). (111) The yellow residue from (1)) was dissolved in 6 N HCl (...) (4.18 128748.doc - 83 - 200848028 mL, 25.08 111 „1〇1) and at 1 〇〇. The solution was concentrated to a volume of about 3 mL and concentrated to a pH of 8 〇 to give a tacky residue (0.41 g). (iv) The residue from (iii) was dissolved in 1 n aqueous sodium hydroxide (2.1) mL, 2.1 mmol), water (214 mL) and p-dioxane (7 j and cooled in an ice bath. Add dibutyl succinate (661 mg, 3 〇〇 2 mm〇i) to this mixture The mixture was stirred and allowed to warm to ambient temperature for 2 hours. The solution was concentrated to remove p-dioxane, diluted with water (5) B), washed with ethyl acetate (3 x 25 mL) and saturated aqueous sodium hydrogencarbonate ( 25 Back-extraction The combined aqueous layers were acidified with a 1 N 5 potassium hydrogen sulfate aqueous solution to a pH of 2-3 and extracted with ethyl acetate (3×5 〇mL). The combined organic extract tk acid Drying, filtration and concentration in vacuo afforded <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; [4-(4-cyclopropyl) -Phenyl)-2,5-di-oxy-imidazolidinyl&gt;#-(2-Fluoro-4-iodo-phenyl)-3-phenyl-butanamine diastereomer by The chromatographic oxime was separated by a 5 to 20% v/v gradient of ethyl acetate in hexanes. The fractions containing the faster moving fractions were collected and concentrated in vacuo. Precipitate to give (2S,3S)_2_[4_(4-cyclopropylphenyl)-2,5.di-oxy-imidazolidin-1-yl]-7V-(2-fluoro-4-iodo-phenyl )-3-phenyl-butanamine, isomer 1. HRMS · Observed mass of C28H26FIN3〇3 + (m+h+): 598.0998; calculated mass · · 598.0998. Example 67 (28'3 8)_2_[ (8) 4-(4-cyclopropyl-phenyl)_2,5-di-oxy-imidazolium-1-128748.doc -84- 200848028 base]-^-(2-fluoro-4-iodine -phenyl)-3-phenyl-butanamine, isomer 2

Prepared by the same procedure as described in Example 66. (2S,3S)_2-[4-(4-Cyclopropyl·phenyl)-2,5-di- oxy- hydroxy phenoxy]-iV-(2-fluoro-4-iodo-benzene The diastereomer of the -3-phenyl-butanamine was separated by ruthenium chromatography eluting with 5 to 20% v/v of ethyl acetate gradient in hexane. The fractions containing the slower moving fraction were collected and concentrated in vacuo to give (2S,3S)-2-[4_(4-i propyl-phenyl)-2,5-di-oxyl-flavor σ sits σ定-i_基]·#-(2-fluoro-4-iodo-phenyl)-3-phenyl-butanamine, isomer 2. HRMS : C28H26FIN303 + observed mass (M+H+): 598.0994; Calculated mass: 598.0998. Example 68

(2S,3S)-2-((R)_4_cyclohexyl_2,5-di-oxyl-imidazolidinyl-yl)_#_(2_fluoro-4-moth-phenyl)-3- Phenyl-butyric acid amine

Prepared by the same method as described in Example 48 except that (R)-second butoxycarbonylamino-cyclohexyl-butyric acid was used instead of (r)-t-butoxycarbonylamino -{4-[2-(tetrahydrogen)-yloxy&gt;ethoxy]-phenyl b-128748.doc -85- 200848028 acid. HRMS : observation quality of C25H28FlN3〇3+ (M+ H+): 564.1 156 ; Calculated mass: 564.1154. Example 69 (28,38)-^(2-Fluoro-4-iodo-phenyl)-2-{4-[4-(2-methanesulfonyl-B () phenyl]-2,5-di- oxy-imidazole pyridine-indole _ bromo 3 phenyl butyl hydrazide, diastereomer 1

Prepared by the same method as described in Example 1, except that (1) 2-fluoro-4-iodoaniline was used in place of 4-bromoaniline in step 2, and (ii) di-dimethoxy group was used in step 4. Alkylamino-[4-(2-methyl-toluene-ethyl)-phenyl]-acetic acid (prepared as described below) replaces (R)-t-butoxycarbonylamino group _4_曱oxyphenylglycine, and (iii) separation of (2S,3S)-;V-(2-fluoro-4-block-phenyl)-2-{ using supercritical fluid chromatography after performing step 6. Non-pair of 4-[4-(2-carbophthalic acid-ethyl)-phenyl]-2,5-di-oxy-imidazolidin-1-yl-3-phenyl-butanamine Isomer. The Chiracel OJ column was used to perform supercritical fluid chromatography separation at 1 bar and 3 (Γ(: 25% ethanol-modified carbon dioxide in acetonitrile to dissolve in 2 ml per minute. The first dissolution) The compound was collected and concentrated in vacuo to give (2S,3 fluoro-4-indole-phenyl)_2_{4_[4_(2-decanesulfonyl-ethyl)-phenyl]-2,5-氧基 _ 味 咬 } } -3- phenyl-butanamine, diastereomer 1. 128748.doc -86- 200848028 Preparation of second butoxycarbonylamino-[4_(2-曱Alkylsulfonyl-ethyl)-phenyl]-acetic acid · (1) to amino-(4-bromo-phenyl)-acetic acid (543 mg, 2.4 mmol), triethylamine (822 pL, 5.9 Addition of di-tert-butyl dicarbonate (mmol) to a mixture of 4-(didecylamino)pyridinium (29 mg, 〇24 mmol) in dioxane/water (2:1, 12 mL) 1.1 g, 5.0 mmol) and the resulting solution was stirred for 3 hours. The reaction was diluted with ethyl acetate (50 ml) and washed with EtOAc EtOAc EtOAc. And the organic layer was dried over sodium sulfate and filtered. The solvent was removed in vacuo to give (4-bromo-phenyl) Alkylamino-acetic acid (780 mg, 1 〇〇〇/0). (2) (4-Bromo-phenyl)-tert-butoxyamino-acetic acid (78〇, 2·4) Ment) dissolved in dimercaptocaramine (15 mL) and added potassium bicarbonate (260 mg, 2.6 mmol), followed by benzyl (281 μΐ, 2.4 mmol) at ambient temperature Stirring was continued for 6 hours. The reaction was poured into water (50 mL) EtOAc (EtOAc)EtOAc. The filtrate was concentrated in vacuo and the residue was crystallised from 1% to hexane to afford (4-bromo-phenyl)-t-butoxycarbonylamino-acetic acid vinegar (500 mg, 50%) 3) (4-Bromo-phenyl)-t-butoxycarbonylamino-benzyl acetate (15 g, 3.6 mmol), mercapto vinylsulfone (4〇6 pL, 4.6 mmol), acetic acid (11 (80 mg, 10 mol%), tri-o-tolylphosphine (217 mg, 20 m〇l%) and triethylamine (2.0 ml '14.3 mmol) combined in acetonitrile (18 mL), degassed And reflux for 8 hours. Add palladium acetate (n) (80 mg, 10 mol%) and three - 128748.doc -87- 200848028

Butoxycarbonylamino-[4-((E)-2-methanesulfonyl-vinyl)-phenyl]-benzyl acetate (1.2 g, 75%). (4) Purification of the third butoxycarbonylamino-[4-((E)-2-methanesulfonyl)-vinyl group contained in methanol/ethyl acetate (3:1, 5〇ml) with nitrogen a hydrogenation vessel of phenyl]-benzyl acetate (1.1 g, 2.5 mmol) and 10% palladium on charcoal (200 mg). The atmosphere on the organic solution was exchanged for hydrogen and the reaction mixture was vigorously stirred at ambient temperature for 3 hours. The reaction mixture was filtered through a pad of celite pad and concentrated in vacuo to give a tris-butoxycarbonylamino group _[4_(2_ 曱石石石-基-ethyl)-phenyl]-acetic acid (8 〇〇mg , 94%). HRMS : Observed mass of C28H28FIN305S+ (M+H+) : 664.0778 ; Calculated mass: 664.0773. 4 NMR (DMSO_d6,300 ΜΗζ) δΗ 10.11 (s,1H), 8.56 (s, 1Η), 5·02 (d, J=11.7 Ηζ, 1Η), 4·41 (s,lH).ppm (characteristic resonance) ). Example 70 (2S,3S)-7V-(2-Fluoro-4-iodophenyl)-2-{4-[4-(2-decanesulfonyl-ethyl)-phenyl]-2, 5-tertiary oxy-imidazole pyridine-1_ kib 3-phenyl-butanamine, diastereomer 2

128748.doc -88- 200848028 Prepared as described in Example 69, with the exception that the second dissolved compound was collected and concentrated in vacuo to give (2S,3S)-;V-(2-fluoro-4-iodo-benzene Methane hydrazide-ethyl)-phenyl]-2,5-di-oxy-imidazolidin-1-yl-3-phenyl-butanamine, diastereomer 2. HRMS : observed mass of C28H28FIN305S+ (m+h+) ·· 664.0763 ; Calculated mass: 664.0773. LC-MS ··]H NMR (DMSO-d6,300 ΜΗζ) δΗ 10.18 (s,1H), 8·61 (s,1Η), 4.93 (s,1Η),4·87 (d,J=11.4 Ηζ , 1Η) ppm (special f sign resonance). Example 71 (2S,3S)-7V-(2,6-Difluoro-4-iodo-phenyl)-2-{(R)-4-[4-(2-methoxy-ethoxy)- Phenyl]-2,5-di-oxy-imidazolidin-1-yl}-3-phenyl-butanamine

Prepared by the same method as described in Example 48 except that (1) 2,6-difluoro-4·iodoaniline was used instead of 2-fluoro-4-iodoaniline and (Π) used (R)_third Butoxylamino-[4-(2-decyloxy-ethoxy)-phenyl]-acetic acid instead of (R)-t-butoxycarbonylamino-{4-[2·(four Hydrogen-piperidin-2-yloxy)-ethoxy]-phenylacetic acid. (R)-Tertibutoxy Roti-fee-[4-(2-methoxy-ethoxy)-phenyl]-acetic acid was prepared as described in Example 48, except that 1-&gt was used. Odor-2-oxoethane instead of 2_(2_bromo-ethoxy)tetrahydropyran. HRMS: observed mass of C28H27F2IN305 + (M+H+): 650·〇952; count 128748.doc -89 - 200848028 Calculated mass: 650.0958. Example 72 (S)-'d-4-iodo-phenyl)-2-{(R:M-[4-(2-hydroxy-ethoxy)-phenyl]-2 , 5 · di-oxy-imidazolidinyl-bubub 3-thiophene-2-yl-propanamide

Prepared by the same method as described in Example 48, except that (1) Step 1 was carried out as follows and (ii) in step 4, bismuth hexafluorophosphate benzotris-1-yl-iV, ^ '^_Bis(tetradecyl) hydrazine was used as a coupling reagent instead of 0-stuppyrazol-1-yltetramethyl hexafluorophosphate. Step 1: To a solution of (S)-2-t-butoxyaminoamino-3- phenan-2-yl-propionic acid (1.1 g, 4.06) under dry argon at -10 °C. Methyl) and 2-fluoro-4-money aniline (8 〇〇 mg, 3.38 mmol) were added to the solution in a mouth-bit (15 mL) with oxychlorination (0.35 mL, 3.72 mmol). The mixture was stirred at -1 °C for 2 hours. Ice water was added after removing the solvent and excess reagent by a rotary evaporator. The mixture was extracted with methylene chloride and the organic layer was washed with EtOAc EtOAc, brine, brine The solvent was removed to give [(S)-1-(2- gas-4-indole-phenylamine)-enyl-2-yl-ethyl]-amino decanoic acid as a yellow viscous oil. Di Erding (1.52 g, 92%), which was used in the next step. LC-MS : Observed mass of C18H20FIN2O3S+ (M+H+): 491; Calculated Mass: 491. 128748.doc • 90 - 200848028 LC-MS : Observation quality of C24H22FIN3〇5S+ (M+H+) : 610 ; Calculation Quality: 6 1 〇. Example 73 (S)-3-(5-Des-σ-Sent-2-L-fluoro-phenyl)-2-{(R)-4-[4_(2·hydroxy-ethoxy)-phenyl ]_2,5-di-oxy-imidazole-1-yl}-propanamide

Prepared by the same method as described in Example 72 except that (S)-3-(5-bromo-nonylphenyl)-2-tert-butoxycarbonylamino-propyl was used in Step 1. The acid replaces (S)-2-tert-butoxycarbonylamino-3-thiophen-2-yl-propionic acid. LC-MS · Observed mass of C24H2iBrFIN3〇5S (M+H+) : 688 ; Calculated mass: 688. Example 74 (S)-2-{(R)-4_[4-((R)-2,3-Dihydroxy-propoxyphenyl) 2,5-di-oxy-imidazolidin-1-yl W W (2-fluoro-4-iodo-phenyl)-3-thiophen-2-yl-propanamide

Prepared by the same method as described in Example U4, except that (1) Dream 1 was carried out as described in Example 72 and (ii) bismuth hexafluorophosphate benzotriazolyl double (four) Amidoxime) is used as a coupling reagent for 128748.doc -91 - 200848028 bismuth hexafluorophosphate-benzotriazol-1-yltetramethylguanidine. LC-MS : Observed mass of C25H24FIN3〇6S+ (Μ+Η+) : 640 ; Calculation Quality: 640. Example 75 (8)-3-(5-&gt;Smelly-17-cephen-2-yl)-2-{(R)-4-[4-((R)-2,3-di-control-propyl Oxy)-phenyl]-2,5-di- oxy--salt bite-1 -yl-random-4-exchange-phenyl)_propanamide

Prepared by the same method as described in Example 114 except that (1) Step 1 was carried out as described in Example 73 and (ii) In step 4, 0-benzotriazol-1-yl hexafluorophosphate was added. (Tetramethylene) hydrazine is used as a coupling reagent instead of benzotriazol-1-yltetramethylphosphonium hexafluorophosphate. LC-MS ·· C25H23BrFIN306S+ Guanlan J mass (Μ+Η+): 718 ; Calculated mass: 71 8. Example 76 (S)-#-(2-Fluoro-4_iodo-phenyl)-2-{(R)-4-[4-(2-hydroxy-ethoxy)-phenyl]-2,5 - Bis-oxy-imidazolidin-1-yl}-3-pyridin-2-yl-propionamide

128748.doc -92- 200848028 was prepared by the same method as described in Example 43, except that (1) (S)-2-D-butyl aryl-amplyl-yl-propyl was used in Step 1. The acid replaces (S)-2_(9//-9-ylmethoxycarbonylamino)-3-naphthalen-2-yl-propionic acid and (ii) proceeds to step 3 as described below. Step 3: 〇°C, to (S)-[l-(2-fluoro-4-iodo-phenylamine fluorenyl)_2_ σ than bit-2-yl-ethyl]-carbamic acid dibutyl ( Trifluoroacetic acid (5 mL) was added to a solution of dichloromethane (5 mL) and the mixture was stirred for 1 hour. The reaction mixture was concentrated in vacuo and the residue was suspended in ice cold water. The aqueous suspension was neutralized with a saturated aqueous solution of sodium carbonate and then extracted with dioxane (three times). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 100% hexanes to 100% ethyl acetate over 40 min. The product-containing fraction was concentrated to give (S)-2-amino-#-(2-fluoro-4-iodo-phenyl)-3-pyridin-2-yl-propanamide (806 mg, as a yellow solid. 85%). LC-MS : Observed mass of C14H13FIN30+ (M+H+) : 386 ; Calculated mass · · 386 〇 LC-MS : Observed mass of C25H23FIN405 + (M+H) ·· 605 ; Calculated mass ·· 605. Example 77 (S)-tV-(2-Mottle-4_ Moth-Phenyl)(R)_4 -[4-(2-Ph-Ethyl-ethyl)-phenyl]-2,5-di-oxyl -taste.坐定定-卜基}-3-(1-oxy-indole-2-yl)-propanamine 128748.doc -93- 200848028

Add 3-oxoic acid (77%, 28 mg, 0·12 mmol) to (S)-JV-(2-fluoro-4_iodo-phenyl)-2-{(R)-4-[ 4-(2-Hydroxy-ethoxy)-phenyl]_2,5-di- oxy-midine-l-yl}-3-indole-2-yl-propionamide (as in Example 76) The preparation) (50 mg, 0.083 mmol) in dichloromethane (4 mL) The reaction mixture was concentrated in vacuo and the residue was purified eluting elut eluting eluting eluting Concentration of the product-containing fractions gave (8)-#_(2_fluoro-4_iodo-phenyl)_2-{(r)_4_[4-(2-trans-ethoxy-y) as a white solid. Phenyl 2,5-di-oxy-imidazolidinyloxy-pyridin-2-yl)-propanamide (40 mg, 78%). LC-MS : Observed mass of c25H23FIN406+ (M+H+) : 621 ; Calculated mass: 621 〇 _ _ _ &quot; sit.定小基}善(2-气-4-峨-phenyl)-3-(S) 2 {(8)-心^^(8)义^二基基-propyloxy^phenyl b^^2 side oxygen ratio Chito-2-ylamine

Prepared by the same method as described in Example 114, except that (1) 128748.doc -94- 200848028, as described in Example 76, step (3) and (u) in step 4, the hexahydrate acid bismuth _Benzotriazole_1-based condition %f-bis(tetramethylene)anthracene is used as a coupling reagent in place of bismuth hexafluorophosphate benzotriazol-1-yltetramethylguanidine. LC-MS: Observed mass of C26H25FIN406+ (M+H+): 635. Calculated mass: 635.口#' Example 79 (S)-'(2-Fluoro-4_iodo-phenyl)-2_{(R)_4-[4_(2-hydroxyethoxyphenyl)-2,5-di-side oxygen Base-imidazolidinyl 3_thiazole_4_yl-propionamide

Prepared by the same method as described in Example 1, except that in step 2, 2-fluoro-4-iodoaniline was used instead of 4-bromoaniline and (s)-2_t-butoxycarbonylamine was used. Substituting 3-(thiazol-4-yl-propionic acid for (2S,3S)-2-t-butoxycarbonylamino-3-phenyl-butyric acid and using (R)_third in step 4 Oxycarbonylamino-{4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl-acetic acid instead of (R)-t-butoxycarbonylamino-[ 4-methoxy-phenyl]-acetic acid. (R)-Tertibutoxycarbonylamino group {4_[2-(tetrahydro-Phenyl-2-yloxy)-ethoxy]-phenyl-acetic acid was prepared as described in Example 48. HRMS : Observed mass of C23H21FIN405S+ (M+H+): 611 〇 253 ; Calculated mass: 611.0256. Example 80

128748.doc -95- 200848028 -4-yl-propylamino]-2,5-di- oxy-imidazole 丨 丨 基 3 3 thiazole

Prepared by the same method as described in Example 79 except that (R)-t-butoxycarbonylamino-[4_(2.methoxy-ethoxyphenyl)-acetic acid was used instead. R)-Tertibutoxymethylamino_{4_[2_(tetrachloro-endoyloxy)·ethoxy]-phenyl-acetic acid. Preparation of (8)-Third as described in Example 48 Oxydoxyamino methoxy-ethoxy) phenyl] acetic acid, except for the use of 1 winter 2 methoxy ethene instead of 2 _ (2_ desert _ ethoxy b tetrachloro brim HRMS · Observed mass of C24H23FIN4〇5s+ (M+H+): 625 〇4〇3 ; Calculated mass: 625.0413. Example 81 ()(2Fluoro 4峨-stupyl)-2-{(R)-4-[4 -(2-hydroxy-ethoxylated phenyl group &gt; 2,5-di- oxy) 1,4-oxazol-1-yl b 3-(3-methyl-3H-imidazole _4_yl) _ propyl hydrazine amine

〇

OH 曰 was prepared by the same method as described in Example 3, except that (1) 2-fluoro-4-indanylamine was used in place of 2_gas_4_indiylamine and (9) was used in the step 128128748.doc '96 - 200848028 (2S)-2-Tertoxycarbonylamino group _3_(3_methyl_3//_imidazole _4_yl)-propionic acid substitution (2S,3S)-2-third butoxide Carbocarbonylamino-3-phenyl-butyric acid. HRMS : Observed mass of C24H24FIN5〇5 + (M+ir): 608.0798 ; Calculated mass: 608.0801. Example 82, (2_I-4-iodo-phenyl+percarbyl-ethoxy)-phenyl]-2,5-di-oxy-imidazolidin-1-ylethylamine

OH was prepared by the same procedure as described in Example 48, except that the (3S,3S)-2-t-butoxy- propylamino-3 was replaced with a third butoxycarbonylamino-acetic acid. Phenyl-butyric acid. HRMS : observed mass of Cl9H17FIN3Na 〇 / (M+Na+) : 536, 〇〇 88 ; Calculated mass: 536.0089. Example 83 (S) Good (2-fluoro_4_iodo-phenyl)-2-{(R)_4-[4_(2·hydroxy-ethoxy)-phenyl]_2,5·di-oxyl -Mixingbite-Buji-Methyl-Butylamine

Prepared by the same method as described in Example 48 except that (S)-2-t-butoxycarbonylamino-3-methyl, τ-deficient &amp; An alternative to 128748.doc -97- 200848028 (2S,3S)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid. LC-MS : Observed mass of C22H24FIN3〇5+: 556 ; Calculated mass · 556 〇^ Example 84 (S)l(2i Iodo-phenyl)-2-{(R)-4-[4-(2-A Oxy-hexyloxy)-phenyl]-2,5-di-oxy-imidazolidin-1-yl-3-methyl-butanamine

Prepared by the same method as described in Example 21 except that (1) in step 1, (S)-2-t-butoxycarbonylamino 3-methyl-butyric acid was used instead of (S)- 2-t-butoxycarbonylamino-3-phenyl-propionic acid and (ϋ) used in the step 4 as 0-benzotriazol-1-ylbis(tetramethylene)phosphonium hexafluorophosphate Coupling reagent instead of hexafluoroantimonic acid benzotriazol-1-yl-TV, tetralinyl record 0 LC-MS: observed mass of C23H26FIN3〇5+ (M+H+): 570; calculated mass: 570 〇 Example 85 (S)-2-{(R)-4_[4-((R)-2,3-dihydroxy-propoxy)-phenyl]_2,5-di-oxy-imidazolidin-1-yl ,(2-Fluoro-4-iodo-phenyl)-3-indolyl-butanamine

128748.doc -98- 200848028 Fine was prepared by the same method as described in Example m, except that (1) the step was carried out as described in Example 83, and (9) the hexafluoropyrene was taken in step 4. The bis-(tetramethylene) oxime is used as a coupling reagent instead of 0-benzotriazolyl tetramethylphosphonium hexafluorophosphate. LC-MS: Observed mass of C23H26FIN306+ (m+h+): 586 ’·Computed mass·· 586. ,. Kaibei example 86 / (8) good (2-fluoro-4 winter phenyl)-3_methyl_2-{4_[4 phenoline _4_ _ ethoxy)-phenyl]-2,5- Bilateral oxy-imidazolium-; 1-yl}-butanamine; compound with acetic acid

Prepared by the same method as described in Example 1, except that (1) Substituting (S)-2-tert-butoxycarbonylamino-3-3-methyl-butyric acid in step 1 (2S, 3S) -2-dibutyloxycarbonylamino-3-phenyl-butyric acid, (丨丨) in step 2 using 2-fluoro-4-aniline instead of 4-bromoaniline and (iii) in step 4 (R,S)-di-dibutoxyamino-[4-(2-morphin-4-yl-ethoxy)-phenyl]-ethylfee is used in place of (R)-didin Oxydoxyaminomethoxyphenylglycine. (R,S)-Tertibutoxycarbonylamino-[4-(2-morpholin-4-yl-ethoxyphenyl)-acetic acid was prepared as follows: (1) to (R)-third Adding 128748.doc -99- to a solution of butoxycarbonylamino-[4-(2-hydroxy-ethoxy)-phenyl]-acetic acid (1.0 g, 3.21 mmol) in methanol (10 mL) A catalytic amount of concentrated sulfuric acid was added. The reaction mixture was stirred at reflux for 3 hours. The solvent was evaporated and crude (R)-t-butoxycarbonylaminohydroxy-ethoxy)-phenyl]-acetic acid methyl ester was obtained. (〇·836 g, 80% yield) was taken to the next step without further purification. (2) Administration of (R)-t-butoxycarbonylamino-[4-(2-hydroxy-ethoxyphenyl)-acetic acid methyl ester (80 mg, 0.25 mmol) in pyridine (1.5 mL) Methane sulfonium chloride (0.023 mL, 0.30 mmol) was added dropwise to the solution. The reaction mixture was stirred at room temperature for 3 hr. The solvent was evaporated and the crude product was purified by silica gel to 3:1 v/v hexane. Purification by elution with ethyl acetate to give (R)-t-butoxycarbonylamino-[4-(2-methanesulfonyloxy-ethoxy)-phenyl]-acetic acid methyl ester as a colorless oil (5〇11^,500/〇 yield). (3) To the (R)-t-butoxycarbonylamino group _[4_(2_nonane) ethoxy-ethoxy group at room temperature To a stirred solution of methyl phenyl]-acetic acid (50 mg, EtOAc) was added EtOAc (EtOAc m. The solvent was evaporated and the crude product was purified by chromatography eluting EtOAc EtOAc EtOAc EtOAc EtOAc. -(2-norlin-4-yl-ethoxy-)phenyl]-acetic acid methyl vinegar (45 mg, 92% yield). (4) to (R)- Tributyloxycarbylamino _[4-(2-morphinyl-ethoxy)-phenyl]-acetic acid methyl ester (45 mg, 〇·11 mm〇i) in decyl alcohol (〇 6 mL) Lithium hydroxide monohydrate (14 3 mg, 0·34 mmol) was added to the stirred solution in water (0.2 mL). The reaction mixture was stirred at room temperature for 3 hr. ,S)-Secondoxyaminoamino-[4_(2-morphin-4-yl-ethoxy)-phenyl]-acetic acid (43 mg, 99% yield) without further purification .doc -100- 200848028 The observed mass (M+H+) sent to the next step: 625.13 18 ; HRMS : C26H31FIN4〇' Calculated mass: 625.1318. Example 87 (SHV-[2-Fluoro-4-iodine -phenyl)_3_methyl_2_(4_{4_[2_(4·methyl_派派小土)ethoxy)phenyl}-2,5-di- oxy- _ 嗤 嗤 小 小Butylide; a compound with acetic acid

OH

Prepared by the same method as described in Example 86, except that (1) used in step 4 (R'S). Third butoxy M-amino group · (4_[2_(4_methyl_略嗓- 1-(1)-ethoxy]-phenyl}•acetic acid instead of (R,s)_t-butoxy-aminoamine[4(2-horrinolin-4-yl-ethoxy)-phenyl-acetic acid Prepared by the same method as in the example (R,S)-t-butoxycarbonylamino[4-(2-morpholino-4-ylethoxy)-phenyl]-acetic acid (R) ,S)·Tertibutoxymethylamino-{4-[2-(4-methyl-Lv)ethoxy]-phenyl-acetic acid, with the exception that 1-methyl group is used in step 3 Piperazine in place of morpholine. HRMS: Observed f amount of C27H34FIN5〇4+ (M+H+): (iv) 1633 Calculated mass: 638.1637. 11 Example 88 (S)-2-(2,5_ di-sideoxy 4 128748.doc -101 - 200848028 A-phenyl)-3-methyl-butanamine

Prepared by the same method as described in Example 1, except that (1) Substituting (S)-2-t-butoxy-carbylamino-3-methyl-butyric acid in step 1 (2S, 3S)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid, (π) in step 2 using 2-fluoro-4-iodoaniline instead of 4-bromoaniline and (iii) in step 4 (R,S)_Tertibutoxycarbonylamino-σ-pyridin-3-yl-acetic acid is used instead of (r)-t-butoxycarbonylamino-4-methoxyphenylglycine . HRMS : Observed mass of C19H19FIN403+ (M+H+): 497.0476 ; Calculated mass: 497.0481. Example 89 4,4,4-Trifluoro-#-(2-Fluoro-4-E-phenyl)-2-{(R)-4-[4-(2-trans-ethoxy-)-benzene -2,5-di-oxy-imidazolidin-1-yl-3-methyl-butanamine

Prepared by the same method as described in Example 72, except that in the first step, (earth)-2-dibutyloxyi-yl- anoylamino-4,4,4-trifluoro-- 3-(Methylbutyric acid) replaces (S)-2-t-butoxycarbonylamino-3-thiophen-2-yl-propionic acid. LC-MS : Observed mass of C22H21F4IN305 + (M+H+) : 610 ; Calculated mass: 61 0 〇128748.doc -102- 200848028 Example 90 (2S,3S)-2-{(R)-4-[4- ((R)-2,^ pendant oxy-(tetra)bita small group}-3-methyl-pentanoic acid (2-fluoro-4-tetraphenyl)amine

Prepared by the same method as described in Example 74, and by the method of formula 4, but the exception is to use (2S, 3S)-2-third butoxide in the bovine 1 ..., 』 』 氧基 氧基 胺 胺 胺 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。. a LC-MS : Observation mass of C24H28FIN306+ (M+H+) : 6〇〇 晰 Clearance: 600 . . Example of a different shell 91 4,4,4-trifluoro 4(2_fluoro.4·iodo-phenyl)·2_{(ιι)_4·[4々_hydroxy·ethyl&amp;yl)-phenyl]-2, 5-tertiary oxy-isoxazole bite + kib% triterpenoid

Prepared by the same method as described in Example 72 except that (±)-2-t-butoxycarbonyl-amino-4,4, 'trifluoro, fluorene" was used in the first step. The acid replaces (S)-2-tert-butoxycarbonylamino-3-thiophene, 2-indolecarboxylic acid. 2-_Tertioxycarbonyl-amino-4,4,fluorenyl-endotrifluorodecyl-butyric acid was prepared as described below. '二气·3- Preparation 2-Tertioxycarbonyl-amino-4,4,4-trifluoro_3•Tri-L-methyl-butyl 128748.doc 200848028 at 〇°C to 4,4, 4,4,,4,,4,-hexafluoro-DL-proline (1·〇g, 4·4 mmol) and sodium carbonate (933 mg, 8.8 mmol) in dioxane (1〇mL) and Ditributyl dicarbonate was slowly added to the solution in water (10 mL). After the addition, the mixture was stirred at a temperature of 12 hours. The reaction mixture was partitioned between water and ethyl acetate and the organic layer was discarded. The organic layer was adjusted to pH <RTI ID=0.0># </RTI> </RTI> <RTI ID=0.0> 4_Trifluoro_3_trifluoromethyl-butyric acid (1.34 g, 96%) LC-MS: Observed mass of C10Hi2F6NO4_ (M_H+) = 324 ; Calculated mass · · 324. Computational LC-MS : C22H18F7IN305+ Observation quality (M+H+)==664 · Quantity·· 664 〇Example 92

By using (S)-2-(9/^荞-9-yl-2-yl-butyric acid instead of (s)-2-(9//- in the same step 1 as described in Example 43 2-Base-propionic acid. Preparation of ethoxybenzene, except for the step group oxime oxycarbonylamino) _3,3·dimethyl methoxycarbonyl amide naphthalene · 128748.doc 104- 200848028 Lc-ms: observed mass of c23h26fin3o5+ (M+H+): 57〇; calculated mass: 570 ° open shell example 93 (8)-M(R)-4-[4_(2 province-ethoxy), Kib 2 , 5^ then oxy" rice bran-1-yl b, 4,4-dimethyl-pentanoic acid (2-fluoro-4-iodo-phenyl)-decylamine

Prepared by the same method as described in Example 43, except that (1) (S)-2-(9//-苐-9-ylmethoxycarbonylamino)_4,4_ was used in Step 1. Dimercapto-2-yl-pentanoic acid replaces (S)-2-(9f苐_9-ylmethoxycarbonylaminonaphthalen-2-yl-propionic acid and (Π) steps * to 7 are carried out as follows :

Step 4: 2-Amino-4,4-dimethyl-pentanoic acid fluoro-4_iodo- phenyl)- decylamine (3 64 mg, 1 mm 〇l), (R)-Terti-butoxy Alkylcarbonylamino-based second butoxy-ethoxy)-phenyl]-acetic acid (1 M in DMF, 1.1 mL, 1.1 mmol), 1-hydroxybenzotriazole (168 mg, M mm〇i) and Hexafluoroacid (9-benzotriazole) was added dropwise to a solution of diisopropylethylamine (〇·53 mL, 3.3 mmol) in TV, TV-dimethylformamide (5 mL). -i_Base - See the solution of bis(tetramethylene) hydrazine (474 mg, 1 · 1 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and the mixture was Washing with water and brine. The organic layer was washed with EtOAc EtOAc EtOAc EtOAc. 2-tert-butoxy-ethoxyl 128748.doc -105- 200848028 yl)-phenyl]-[(S)-i_(2-fluoro-4-iodo-phenylaminecarbamyl)_3,3- Di-decyl-butylamine-mercapto-l-methyl}-carbamic acid tert-butyl ester (652 mg, 91%). LC-MS: observed mass of C32H45FIN3〇6+ (M+H+) 714; Calculated mass: 714 〇Step 5: to {(R)_[4_(2_Tertioxy-ethoxy)-phenyl(2-fluoro-4-indolyl-phenylaminomethyl) _3,3_Dimethyl-butylamine-mercapto]-methyl}-amino decanoic acid tert-butyl ester (652 mg, 〇·91 mmol) was added to the solution in acetonitrile (6 mL) 4 N hydrogenated hydrogen in methane (1 mL, 4 mmol) and the mixture was stirred at 40 ° C for 30 min. The reaction mixture was concentrated in vacuo and the residue was suspended in ice cold water. The sodium aqueous solution was neutralized to an initial pH, then extracted with dichloromethane (three times). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. 1〇〇% of the two gas to a 10% methanol / 90% dioxane methane gradient elution purification. Concentration of the product containing fractions to obtain (S)-2-{(R)-2-amino-2-[4 -(2-tatabutoxy-ethoxy)-phenyl]-acetamido}-4,4-dimethyl-pentanoic acid (2-fluoro-4-iodo-phenyl)-decylamine (490 mg, 87%) LC-MS · Observed mass of C27H38FIN3〇4+ (Μ+Η+)=ό14 ; Calculated mass: 614 〇 Step 6: at -3 5 ° C under a dry argon atmosphere with stirring for 1 Torr to diphosgene (41 μί, 0.34 mmol) in 1:1 v/v toluene/tetrahydrofuran. Solution (8)-2-{(11)-2-amino-2-[4-(2-di-di-butoxy-ethoxy)-phenyl]-B was added dropwise in a total of 18 1111〇醯Amino}-4,4-dimercapto-pentanoic acid (2-fluoro-4-indolyl-phenyl)-decylamine (300 mg, 0.49 mmol) and n,N-diisopropyl 128748.doc-106 - 200848028 Ethylamine (260 pL ' 1.47 mm〇1) in tetrahydrotetramine (9... solution). After a further 45 minutes, ice was added and the reaction mixture was stirred vigorously and warmed to ambient temperature. The reaction mixture was poured into water, and extracted with ethyl acetate (twice), and the combined organic layers were washed successively with water (twice), 〇1 M aqueous hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and brine. Drying over sodium sulfate, filtration and concentration in vacuo to give (S)-2-{(RM-[4 </RTI> <RTIgt; -isoxazin-1-yl}-4,4-dimethyl-pentanoic acid (2-fluoro-4-indolylphenyl)-decylamine (295 mg '95%) 'can be used without further purification In the subsequent steps. LC-MS : Observed mass of C28H36FIN3〇5+ (M+H+): 64〇; calculated mass: 640 〇Step 7: at 0°C, under (S)-2_{(R)_4_ under dry argon atmosphere [4_(2_1,1-butoxy-ethoxy)-phenyl]_2,5-di-oxyl _ _ _ _ _ _ _ _ 4, 4- dimethyl-pentanoic acid (2 _ _ 4_Iodo-phenyl)-decylamine (295 mg, 〇46 mmol) in dichloromethane (3 mL) was slowly added tridecyl decyl iodide (183 μιη, 1.3 mmol) to di- methane ( Solution in 1 mL). The reaction mixture was stirred at ambient temperature for 2 hours. Methanol (〇·5 mL) was added to stop the reaction. The reaction mixture was extracted with EtOAc (EtOAc)EtOAc. The residue was purified by silica gel chromatography eluting with EtOAc EtOAc EtOAc. The product-containing fraction was concentrated to give (S)-2-{(R&gt;4-[4-(2-hydroxy-ethoxy)-phenyl]_2,5-di- oxy-imidazole as a white solid. Acridine-1-yl b, mercapto-pentanoic acid (2-fluoro-'iodo-phenyl)-decylamine 128748.doc -107- 200848028 (126 mg, 47%). LC-MS : C24H28FIN305+ Observed mass (M+H+): 584; calculated mass: 584. Example 94 (S)-2-5 isopropyl propyl-7V_(2-Ga-4-E-phenyl)-2-{(R)-4 -[4-(2-^i-yl-ethoxy)-benzyl]-2,5-di-oxyl-scented sputum-1 -yl}-ethonamide

Prepared by the same method as described in Example 48 except that (1) (S)-T-butoxycarbonylamino-cyclopropyl-acetic acid was used in step 1 instead of (2S,3S)-2- Third butoxycarbonylamino-3-phenyl-butyric acid and (ii) used in the step 4 as 0-benzotriazol-1-yl AT-bis(tetradecyl)fluorene hexafluorophosphate The coupling reagent replaces cesium hexafluorophosphate-benzotriazol-1-yltetradecyl fluorene. LC-MS: Observed mass of C22H22FIN3 〇5+ (M+H+): 554. Calculated mass: 554. Example 95 (S) -3-D-propyl-7V-(2-gas-4-moth-phenyl)-2 - {(R)-4-[4-(2-^l-ethoxy) -phenyl]-2,5-di-oxyl-117 m ° sit-l-l-yl}-propionic acid amine

128748.doc 108-200848028 was prepared by the same method as described in Example 48 except that (1) (S)-2-t-butoxycarbonylamino-3-3-cyclopropyl was used in step 1. Propionic acid replaces (2S,3S)-2-secondbutoxycarbonylaminophenyl-butyric acid and (丨丨) in step 4 hexafluorophosphoric acid (9·benzotriazole-^ double (four sub- Methyl) hydrazine is used as a coupling reagent to replace hexafluoro-storage σ•benzotriazole small tetramethyl hydrazine. LC-MS : C23H24FIN305 + observed mass (Μ+Η+) : 568 ; calculated mass: 568 . Example 96 (S)-3-Cyclohexyl-#-(2-fluoro-4-E-phenyl)_2-{(r)_4-[4-(2-hydroxy-ethoxy)-phenyl]- 2,5-di- oxy-flavor α-bite-kib propylamine

Prepared by the same method as described in Example 48, except that (1) in step 1, (S)-2-t-butoxycarbonylamino-3-3-cyclohexyl-propionic acid was used instead (2S, 3S) -2-dibutyloxy 1k-amino-3-phenyl-butyric acid and (丨丨) is charged with hexa- 1 &lt;9-benzotriazol-1-yl-^ in step 4. #,,^^_Bis(tetramethylene) hydrazine is used as a coupling reagent instead of bismuth hexafluorophosphate-benzotriazine _ _ M tetradecyl hydrazine. LC-MS ·· C26H30FIN3O5 observation quality (M+H+) ·· 610 ; calculated mass: 610. Example 97 128748.doc -109- 200848028 (2S,3R)_7V-(2-fluoro-4-c-phenyl)-2-[(R)-4-(4-carbyl-phenyl)_2 5- Bis-oxy-imidazolidin-1-yl]-3-methoxy-butanamine

Prepared by the same method as described in Example 1, except that (1) was replaced with (2S,3R)-2-t-butoxycarbonylamino-3-methoxy-butyric acid in Step 1. (2S,3S)-2-Tertoxycarbonylaminophenyl-butyric acid, (Η) In step 2, 2-fluoro-4-indanylamine is used instead of 4-indiylaniline, In step 4, hexamethylene hexafluoroantimonate is used as a coupling reagent to replace hexacolic acid (9·benzotris-1 -yl-w-tetradecyl) And (iv) replacing (R)-t-butoxycarbonylamino-4-methoxy with (R)-t-butoxycarbonylamino-4-hydroxyphenylglycine in step 4. Phenylglycine. LC-MS: Observed mass of C2〇H2〇FIN305+ (M+H+): 528; Calculated mass Quantities: 528. Example 98 (2S,3R)-7V-(2-Fluoro-4 -iodo-phenyl)-2-{(R)_4-[4-(2-hydroxy-ethoxy)-phenyl]-2,5-di-oxy-imidazolidin-1-yl}-3 -methoxy-butylamine

128748.doc -110- 200848028 was prepared by the same method as described in Example 48 except that (1) (2S,3R)-2-Tertoxycarbonylamino group _3-曱 was used in Step 1. Oxy-butyric acid replaces (2S,3S)-2·t-butoxycarbonylaminophenyl-butyric acid and (ii) benzotriazol-1-yl hexafluorophosphate in the fourth step (fourth Indenyl hydrazine is used as a coupling reagent instead of bismuth hexafluorophosphate. Sit on the small base - N, N, Nf, Nf - four f I Su. LC-MS · C22H24FIN3〇6+ observed mass (M+H+): 572 ; calculated mass: 572 .

Example 99 (2S,3R)-2-{(R)-4-[4-((R)-2,3-Dihydroxy-propoxyphenyl]_2,5-di-oxy-imidazole- 1-yl}_#-(2-fluoro-4-iodo-phenyl)_3_methoxy-butanamine

Prepared by the same method as described in Example 114 except that (1) v was replaced with (2S,3R)-2-t-butoxycarbonylamino-3-3-methoxybutyric acid in Step 1. (2S,3S)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid, (11) 2-chloro-4-iodoaniline in place of 2-chloro-4-iodoaniline in step 2 And (in) in step 4, ruthenium hexafluorophosphate benzotriazole-diyl bis(tetramethylene) hydrazine is used as a coupling reagent to replace the hexamethic acid benzotriazine small group see WW - Tetramethyl hydrazine. LC-MS ·· C23H26FIN3CV observation mass (m+h+): 6〇2; calculated mass: 602. 128748.doc -111. 200848028 Example 100 (2S,3R)-3-Alkyloxy winter {called 仙仙)...·二轻基-propyloxyphenyl]-2,5-di-oxy-imidazole Acridine-kappa}_沁(2_fluoro_heart iodine-phenyl)-butyric acid amine

Prepared by the same method as described in Example 43, except that (1) (2S,3R)-3-benzyloxy, 2-(9仏-ylmethoxycarbonylamino)-butyl was used in Step 1. The acid replaces (S)-2-(9//-|^9_yloxycarbonylamino)_3_naphthalene-2-yl-propionic acid and (ii) after step 3 as described in Example 114 step. LC-MS · C29H3 〇 FIN307+ observed mass (M+H+): 678 ; calculated mass: 678 . Example 101

(28,311)-2-{(11)-4-[4-((11)-2,3-dihydroxy.propoxy)-phenyl]_2,5-di-oxy-imidazolidin-1- Base}-&gt;1-(2-fluoro-4-iodo-phenyl)_3_hydroxy-butanamine

Prepared by the same method as described in Example 43, except that (1) used in step 1 (28,311)-3-t-butoxy-2-(9-ylmethoxycarbonylamino)-butyl Acid substitution (S) 2 - (9 / / _ _ 9 _ methoxycarbonylamino group 128748. doc - 112 - 200848028 naphthalen-2-yl-propionic acid and (Π) steps as described in Example 114 Steps after 4. LC-MS: Observed mass of C22H24FIN307+ (M+H+): 588; Calculated mass: 588. Example 102 (S)-7V-(2-Fluoro-4-c-phenyl)-2-{ (R)-4-[4-(2-trans)-ethoxy)phenyl]-2,5-di-oxy-miso-1-yl}-4-phenyl-butylamine

Prepared by the same method as described in Example 72 except that (S)-2-t-butoxycarbonylaminophenyl styryl-2-yl-butyric acid (S) was used in +1 2-tert-butoxycarbonylamino-3-thiophen-2-yl-propionic acid. LC-MS: Observed mass of C27H26FIN305+ (M+H+): 618; calculated mass · · 618. Example 103 (S)-iV-(2-Fluoro-4-anthracene-phenyl)-2-{(R)-4 -[4-(2-thyl-ethoxy)#]], 5-tertiary oxy-imidazolidin-1-yl}-4-methanesulfonyl-butane

128748.doc -113 - 200848028 was prepared by the same method as described in Example 43, except for the step

Propionic acid.

Quality: 620. Example 104 (S)-2-{(R)-4-[4-(2-hydroxy-ethoxy)-phenyl&gt; 2,5-di-oxyl-imidazolidinyl-l-yl} Diacid 5-nonylamine 1-[(2-fluoro-4-iodo-phenyl)-decylamine]

Η2ν \〇 was prepared by the same method as described in Example 72 except that the (S)-2-t-butoxycarbonylamino-4-aminemethylmercapto-butyric acid was used in the step 1. (S)_2-Tertibutoxycarbonylamino-3_thiophene-2-yl-propionic acid. i LC_MS : observed mass of C22H23FIN406+ (Μ+Η+) : 585 ; calculated mass: 585 . Example 105 (S)-;V-(2-chloro-cardioiodo-phenyl)-2-{(R)-4-[4-(2-hydroxy-ethoxy)-phenyl]-2,5 - One side oxy-salt sigma-l-yl}-3-phenyl-propanol

128748.doc -114- 200848028 was prepared by the same method as described in Example 3 except that (1) 2-fluoroiodo-aniline was used instead of 4-bromo-2-chloro-aniline in step 1 and (Η) Substituting (S)-2-t-butoxycarbonylaminophenyl-propionic acid for the (S,s)-2-t-butoxyamino-3-phenyl-butyric acid in step 1. . HRMS · C26H24C1IN305 + observation quality (M+H+): 620.0442; calculation quality · · 620.0444. Example 106 Chloro_4_iodo_phenyl)_2-{(Ιι)_4_[4·(2•曱-oxyethoxy)-phenyl]_2,5-di-oxy-imidazolidin-1- Keb 3-phenyl-propanamide

Prepared by the same method as described in Example 3, except that (1) 2-chloro-4-iodo-aniline was used instead of 4-bromo-2-chloro-aniline in step y, (Η) in step 1. Substituting (S)-2-t-butoxycarbonylaminophenyl-propionic acid for (S'S)-2-secondbutoxycarbonylamino-3-3-phenyl-butyric acid and (丨丨丨) In step 2, (R)-second butoxycarbonylaminomethoxy-ethoxylated phenyl l-acetic acid is used instead of (R)-t-butoxycarbonylamino group _[4_(2_ Tributoxy-ethoxy)-phenyl]-acetic acid. The third butoxycarbonylamino-[4-(2-methoxyethoxy)-phenylacetic acid was prepared as described in Example 8A. HUMS · C27H26ClIN3〇5 + observation quality (M+H+) · 634 〇6〇2 ; Calculated quality: 634.0600. Example 107 128748.doc •115- 200848028 US "(chloro-4-iodo-phenyl)_2-{(r)_4_[4_((r)_2,3_dihydroxy-propoxy)-benzyl]々,5 - two-sided oxy-flavor]-yl}-3-phenyl-propanol

The residue was prepared by the method described in (4) as in Example 3, except that (1)

, using 2-gas-4-iodo-aniline instead of 4-bromo-2-gas-stupamine, (ϋ) using fQ, Λ (trityloxycarbonylamino-3-phenyl) in step - propionate (S,S)-2-second y-methoxyamino-3-yl-butyric acid and (in) in step 2, using a second butoxycarbonylamino group _ [4_((s)_2,2_Dimethyl_[丨,3]dioxoylmethoxy)phenyl]-acetic acid instead of (R)-t-butoxycarbonyl month r (2苐二Butoxy-ethoxy)-phenyl]-acetic acid. Prepared as described in Example 114 and used (R)-t-butoxycarbonylamino-[4_((s)_2,2-dimethyl -[丨,3] Dioxolane································ 2S,3S),_(2-chloro-4-iodo-phenyl)-2-[(R)-4-(4-methoxy-phenyl)-2,5_one-oxy-imidazole- 1-yl]_3_phenyl-butanamine

128748.doc -116- 200848028 was prepared by the same method as described in Example 1, except that (1) 2-chloro-4-iodoaniline was used in place of 4-bromoaniline in step 2 and (ii) in step 4 The (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride is used as a coupling reagent instead of bismuth hexafluorophosphate-benzotriazol-1-yltetramethylguanidine. HRMS : Observed mass of C26H24C1IN304+ (M+H+) : 604.0496 ; Calculated mass: 604.0495. Example 109 (2S,3S)'-(2-Gas_4_iodophenyl)-2-[(R)-4-(4-cyclopropylmethoxy-phenyl)-2,5-di-side Oxy-imidazolidine-1-yl]-3-phenyl-butanamine

Prepared by the same method as described in Example 3 except that 2-chloro-4-aniline was used in place of 2-ox-4-bromoaniline in step 1 and (R)_ was used in step 2. Tributoxycarbonylamino-(4-cyclopropylmethoxy-phenyl)-acetic acid instead of (R)-second butoxycarbonylamino group _[4_(2_t-butoxy-ethoxy Base) _ phenyl]-acetic acid. Preparation of (R)-t-butoxycarbonylamino-{4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl-acetic acid by the method of Example 48 A similar method is used to prepare (R)-t-butoxycarbonylamino-tert-butoxy-ethoxy)-phenyl]-acetic acid, with the exception of using cyclopropylmethyl bromide instead of 2 - ( 2 - &gt; stinky - ethoxy) _ tetrachloro british. HRMS · Observational mass of C29H28C1IN304+ (Μ+Η+): 644.0799. Calculation quality: 644.0808. 128748.doc -117- 200848028 Example 110 (28,3 8)-#_(2-Ga-4-iodo-phenyl) Winter {(11)_4-[4_(2-Hydroxy-ethoxy)-benzene Base]-2,5·di-oxy-imidazolidin-1-yl b-3-phenyl-butanamine

Prepared by the same method as described in Example 48 except that 2-fluoro-4-iodoaniline was used in the second step instead of 2-fluoro-4-indolylamine. HRMS : Observed mass of C27H26CllN3〇5+ (M+H+) ·· 634.0597 ; Calculated mass: 634.0600. LC-MS (reverse phase HPLC, C18 column, water / acetonitrile gradient): Rt = 2.36 min, observed mass of C27H25ClIN3Na05+ (M+Na+): 656; Calculated mass: 640 NMR (DMSO-d6, 300 ΜΗζ) δΗ 9.85 (s, 1H), 8.56 (s, 1H), 4.95 (d, 1 · 5 Ηζ, 1 Η) ppm (characteristic resonance). Example 111 (2S,3S)-iV-(2- gas-4-oxime-phenyl)-2-{(S)-4_[4-(2-trans-ethoxy-phenyl)-phenyl]-2 , 5-dioxy-imidazolidine-1-ylbu-3-phenyl-butanamine

(2S,3S)-N-(2-Chloro-4-indole-phenyl)_2-{(r)_4-[4-(2-trans-ethoxy-128748.doc-118-200848028 base)_ A solution of phenyl]β2,5-di-oxy-isoxazolidine-based 3·phenyl-butanamine (prepared as described in Example 110) (50 mg, 0 079 mm〇1) was dissolved in methanol. (3 mL) and stirred at ambient temperature for 4 days. The resulting mixture of isomers was condensed in the true two and then subjected to supercritical fluid chromatography using a Chiracel OJ column to modify ethanol at 100 bar and 3 (35% v/v in acetonitrile at TC). The carbon dioxide solution was purified by dissolving in 2 ml per minute. The first dissolved compound was collected and concentrated in vacuo to obtain (28, 38) _1 (2-chloro-4-phenyl-phenyl)-2-{(S)-4-[ 4-(2-.yl-ethoxy)-phenyl]_2,5-di-oxy-imidazolidinyl}-3-phenyl-butanamine (14.6 mg, 29%). Second dissolving compound Equivalent to (2S,3S)_N-(2-gas 1 iodine-phenyl)(8)_4_[4_(2_transyl-ethoxy)-phenyl]-2,5-di-oxy-imidazole 丨_ kib 3 phenyl-butanamine (18 · ι mg, 36%) LC-MS (reverse phase HPLC, C18 column, water / acetonitrile gradient): Rt = 2.40 min, observed mass of C27H25ClIN3Na05 + (M +Na+) : 656 ;Computed mass: 640 〇4 NMR (DMSO-d6, 300 ΜΗζ) δΗ 9.98 (s,1H), 8.61 (s,1H), 4.81 (d, J=11.8 Ηζ,1Η) ppm (features Resonance). Example 112 (2S,3S)-7V-(2- gas-4-峨-phenyl)_2_{(r)-4_[4-((R)-2-yl-propyl-propoxy)_ Phenyl]-2,5-di-sideoxy-imidazolium q-yl Phenyl-butanamine

128748.doc 119· 200848028 was prepared by the same method as described in Example 3, except that (1) 2-furo-4-indenylamine was used in step 1 instead of 4-di- 2' chloro-aniline ( Ii) using (R)-t-butoxycarbonylamino group [heart ((r)_2-hydroxy-propoxyphenyl]-acetic acid instead of (R)_t-butoxycarbonylamine in step 2 Base_[4_(2_Tertoxyethoxy)-phenyl]-acetic acid. Preparation of (r)-t-butoxycarbonylamino-[4_((κ)-) as described in Example 48 2-hydroxy-propoxy)-phenylacetic acid, with the exception that (R)-2-methyl-oxo is substituted for 2-(2-bromo-ethoxy)-tetrahydropyran. HRMS · C28H28ClIN3〇 5 + observation mass (Μ+Η+): 648·〇755; calculated mass: 648.0757. Example 113 (2S, 3S)-7V-(2-gas-4-iodo-phenyl)_2-{(R) -4-[4-(2_ methoxy-ethoxyl·phenyl]-2,5-di-oxy-imidazolidinium; 1_yl}_3_phenyl-butanamine

Prepared by the same method as described in Example 3 except that (1) 2-furo-4-iodo-phenylamine was used in place of 4-bromo-2-chloro-aniline in step 1 and (ii) in step 2. Substituting (R)-t-butoxycarbonylamino-[4-(2-methoxy-ethoxy)-phenyl]-acetic acid for (R)-t-butoxycarbonylamino-[4 2-tert-butoxy-ethoxy)-phenyl]-acetic acid. (r)-Tertiaryoxylkamino-[4-(2-methoxy-ethoxy)-phenyl]-acetic acid was prepared as described in Example 80. HRMS: Observed mass of C28H28ClIN3〇5 + (M+H+): 648.0746; count 128748.doc -120- 200848028 Calculated mass: 648.0757. Example 114 (2S,3S)-7V-(2-Ga-4-iodo-phenyl)-2-{(R)_4_[4-((R)-2,3-dihydroxypropoxy)-benzene -2,5-di-oxy-imidazolidin-K-pyridyl 3-phenyl-butanamine

Prepared by the same method as described in Example 110, except that (1) in step 4, (R)-t-butoxycarbonylamino-[4-((S)-2,2·2 Mercapto-[1,3]dioxolan-4-ylmethoxy)-phenyl]-acetic acid (prepared as described below) in place of (R)-t-butoxycarbonylamino-{4-[ 2-(tetrahydro-pyran-2-yloxy)-ethoxy]phenylacetic acid, (ii) (2S,3S)-2-{(R)-2-amine before proceeding to step 6. Base-2-[4-((R)-2,3-di-propyl-propyl)-phenyl]-acetamido}}4-(2-a-4-iodo-phenyl)- 3-phenyl-butanamine is temporarily protected as (2S,3S)-2-{(R)-2-amino-2-[4-((S)-2,3-bis-tridecyldecaneoxy -propoxy)-phenyl]-acetamido}} -7V-(2·gas-4-moth-phenyl)-3-phenyl-butanamine (as described below), and Iii) In step 6, carry out (2S,3S&gt; 2-{(R)-4-[4-((S)-2,3-bis-trimethyldecyloxy-propoxy)-phenyl Acid-catalyzed hydrolysis of -2,5-di-oxy-imidazolium-i-based gas-4-iodo-phenyl)-3-phenyl-butanamine (as described below) followed by (2S) ,3S)-7V-(2-Ga-4-iodo-phenyl)_2_{(r)_4-[4-((R)-2,3-dihydroxy Purification and separation of -propoxy)-phenyl]-2,5-di-oxy-imidazolidin-1-yl}-3-phenyl-butanamine. 128748.doc -121 - 200848028 Preparation of (R)-dibutyloxy-Wilylamino-[4-((s)_2,2-dimethyl-[ι 3] Dioxol-4-yl Oxy)-phenyl]-acetic acid: (1) at 0 ° C under a dry argon atmosphere to (Sy 2,2-diindolyl, 3-dioxolane-4-methanol (5.22 g ' 39.5 mmol), a solution of dichloromethane (6 mL)* was added triethylamine (11 mL, 79 mmol) and 2,5-dichlorosulfonyl chloride (10.18 g, 41·5 mmol). The mixture was stirred and slowly warmed to ambient/JBL separator. The reaction mixture was diluted with dichloromethane and washed with water. The aqueous layer was separated and washed once with methane methane. Aqueous (once), brine (primary), dried over sodium sulfate, dried over EtOAc EtOAc (EtOAc) Purification by gradient elution of ethyl acetate to give (2,5-dichloro-benzenesulfonic acid (R)-2,2-dimethyl-[1,3]«-oxopentan-4-yl as a colorless solid A g (11.06 g, 82%). (2) at 0 ° C ° C, in a dry argon atmosphere, to the third Add sodium hydride to a stirred solution of oxycarbonylamino-(4-.yl-phenyl)-acetic acid (1·4 g, 5.24 mmol) in anhydrous N,N-dimethylformamide (25 mL) 60% suspension in mineral oil) (290 mg, 〇· 12 mmol) and spoiled the mixture for 15 minutes under 〇. 2,5-di-gas-benzenesulfonic acid (r) 2,2-dimethyl _[1,3]dioxolan-4-ylmethyl ester (2.14 mmol, 6.29 mmol) was added to the reaction mixture to give a yellow solution. The yellow solution was stirred at ambient temperature for 5 minutes and then warmed to 100 ° C. The reaction mixture containing the heavy precipitate was cooled to ambient temperature, diluted with ethyl acetate, cooled to dryness, and treated with an equal volume of water. The stirred mixture was acidified to pH Η = 4 with 1 HCl aqueous solution. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was combined with water (tri), dried over sodium sulfate, filtered through a pad of silica gel and concentrated in vacuo. (R)_Tertibutoxycarbonylamino-[4-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl) Oxy)-phenyl]-acetic acid (1.96 g, 96%) which was of sufficient purity to be used in step 4 without additional purification. Preparation of (2S,3S)-2-{(R)-2-amine Benzyl-2-[4-((S)-2,3-bis-trimethylglyoximeoxy-propoxy)-phenyl]-acetamido}-#-(2-chloro-4-pyribyl) -Phenyl)-3-indolyl-butanamine: Add triethylamine (277 μί, 1.98 mmol) and trimethylchlorodecane (23 〇KL, 1.76 mmol) to (2S,3S)-2-{ (R)-2-Amino-2-[4-((R)_ 2,3-di-propyl-propoxy)-phenyl]-acetamido-based group|(2-gas-4_VCD -Phenyl)-3_phenyl-butanamine (330 mg, 0.44 mmol) in EtOAc (3 mL). The resulting suspension was diluted with ethyl acetate (50 mL) and brine (2 EtOAc). The combined brine layers were back-extracted with ethyl acetate (2 EtOAc (5) EtOAc). 11)-2-Amino-2-[4-((8)-2,3-bis-trimethyldecyloxy-propoxy)-phenyl]-acetamido-based ## (2_ Gas_4_iodo-phenyl)_3_phenyl-butanamine (330 mg, 96%), which was of sufficient purity to be used in step 6 without additional purification. Hydrolysis of (2S,3S)-2-{(R)_4-[4_((8)-2,3_bis-trimethylsulfanyloxy-propoxy)phenyl]-2,5-di-oxyl ♦ sitting bite + base} good (2, gas hail-phenyl)-3-phenyl-butanamine: followed by cyclization (2s, 3s)_2_{(r) using a method similar to that described in Example 6. _2_ 128748.doc -123 - 200848028 Amino-2-[4-((S)_2,3-bis-trimethyldecyloxy-propoxy)-phenylethylamino} Chlorine_4_峨_phenyl)_3•phenyl_ butylamine

(jS,3S)-2-{(RM-[4'((S)-2,3-bis-tridecyldecyloxypropoxy)-phenyl]-2,5·di- oxy 1 Sputum bite}|(2_gas_4_峨phenyl)_3·Phenylbutyramine is dissolved in ethyl acetate (5〇mL) and with Ην/ν.Μ aqueous hydrochloric acid/saline at ambient temperature The mixture was vigorously mixed for 5 minutes to effect the removal of the trimethyl sulphate protecting group. The layers were separated and the aqueous layer was taken with ethyl acetate (2×50 mL). The combined ethyl acetate layer was dried over sodium sulfate and filtered. And concentrated in vacuo, followed by final purification by gelatin chromatography by gradient elution between 100% dichloromethane and 3% dichloromethane in methanol with iv% v/v. After dissolving, the glassy residue was dissolved in dichloromethane (5 mL), diluted with diethyl ether (2 mL) and hexane (15 mL) was added to precipitate (2S,3S)j-(2-chloro 4-iodo-phenyl)-2-{(R)_4-[4-((R)-2,3-dihydroxy-propoxy)-phenyl]·2,5-di-oxy- Imidazo-1-yl}-3-phenyl-butanamine, which was filtered and dried in vacuo to give a colourless solid (EtOAc, EtOAc, Observation mass: 664.0703; calculated mass: 664.0706 ° Example 115 (2S, 3S)-7V-(2-chloro-4-iodo-phenyl)-2-{(S)-4-[4-((R)- 2,3-dihydroxy-propoxy)-phenyl]-2,5-di-oxy-imidazolidin-1-yl}-3-phenyl-butanamine

128748.doc -124- 200848028 will come from the preparation of (2S,3S)|(2•gas_4_iodine_phenyl)_2_{(r)_4_[4_ ((R)-2,3_di-based-propoxy Base) _phenyl]·2,5. Two-side oxy-mi. The filtrate I of the final purification step of sitting on a small base}-3-phenylbutylide (prepared as described in Example 114) was reduced to (2S, 3S)|(2_chloro-4-moth-phenyl) _2_{(r)_4_[4_((8)-2,3-di-propyl-propoxy)-phenyl]·2,5·di-oxyl-flavor. Sit _ _ base -3- phenyl-butanamine. The diastereomers were separated by supercritical fluid chromatography using a Daicel OD column to dissolve in 4% acetonitrile/ethanol of 1:1 ν/ν in carbon dioxide.

HRMS : Observed mass of C28H28C1IN3〇6+ (Μ+Η+) : _ surface; calculated mass: 664.0706. Example 116 (2S,3S)m4-峨-phenyl)|{(κ)_4·[4_((8)_2,3_dihydroxy-propoxy)-phenyl]-2,5-di- oxy" rice bran Bite small base}_3·phenyl·butanide

Prepared by the same method as described in Example 114 except that (R)-t-butoxycarbonylamino group _[4_gr)_2,2-didecyl-[1,3 was used in step 4. Dioxol-4-ylmethoxy)phenyl]-acetic acid instead of (R)-t-butoxycarbonylamino-[4-((S)-2,2-diinyl-[ 1,3] Dioxolane-4-ylmethoxy l.phenyl]-acetic acid. By the preparation of (R)-t-butoxycarbonylamino-[4-((S)) -2,2-Dimethyl_π,3]dioxolan-4-yloxy)-phenyl]-acetic acid The same procedure was used to prepare (R)-t-butoxycarbonylamine 128748. Doc -125- 200848028 base _[4-((R)-2,2·dimethyl^,3]dioxolan-4-ylmethoxy)phenyl]-acetic acid' but the exception is for use ( R&gt;2,2-Dimercapto 4,3-dioxolan-4-methanol S (8)-2,2-methyl-1,3-dioxolane-4-methanol HRMS: Observed mass of C28H28C1IN306 + (M+H+) : 664.0710 ; Calculated mass: 664.0706. Example 117 (23,38)-2-[(11)-4_(4-{[bis-(2-hydroxy-ethyl)- Amidino]-methoxy}-phenyl)-2,5-di-oxy-imidazolidin-1-yl]-τν-(2-chloro-4-iodo-phenyl)-3-benzene Butylamine

Prepared by the same method as described in Example 1-9, except that _[4-(2-{bis-[2-(t-butyl-dimethyl-decyloxy)) was used. -ethyl]•amino}-ethoxycarbonyl)-phenyl]-tert-butoxycarbonylamino-acetic acid instead of (R)_t-butoxycarbonylamino-(4-cyclopropylmethyl) Oxy-phenyl)-acetic acid. Preparation of a third butyl-dimethyl-decyloxy)-ethyl]-amino}-ethyloxy)-phenyl]-tert-butoxycarbonylamino-acetic acid as described in Example 48, The exception is the use of bis-[2-(t-butyl-didecyl-decyloxy)-ethyl]-2-chloro-acetamide instead of 2-(2-bromo-ethoxy)-tetrahydro Piper. HRMS : M.sub. Example 118 128748.doc -126- 200848028 (S)-7V-(2-chloro-4-indolyl)-2,5-di- oxycarbazole biting small base}-3_嗟salt_4_yl_ Propionate

Prepared by the method as described in Example 4 (IV), except that (1)

Substituting (S)-2-t-butoxycarbonylamino-3-3-thiazol-4-yl-propionic acid for the substitution of (2S,3S)-2_t-butoxycarbonylaminophenyl-butyl acid. HRMS : Observed mass of C23H21C1IN405S+ (M+H+): 626.9964 ; Calculated mass: 626.9961. Example 119 (S)-; V_(2-chloro-4-iodo-phenyl)-2-[(R)-4-(4-cyclopropyldecyloxy-phenyl)_2,5-di-side oxygen Base-imidazolidin-1-yl]-3-indolyl-butanamine

Prepared by the same method as described in Example 3 except that (1) in step 1, 2-chloro-4-iodo-aniline was used instead of 4-bromo-2-chloro-phenylamine, (Π) in step 1. Substituting (S)-2-t-butoxycarbonylamino-3-methyl-butyric acid for (s,s)-2-tributoxycarbonylamino-3-phenyl-butyric acid and Iii) using (R)-t-butoxycarbonylamino-(4-cyclopropyldecyloxy-phenyl)-acetic acid (prepared as described in Example 109) in place of (R)_ Tributoxycarbonylamine 128748.doc -127- 200848028 benzyl-[4-(2-t-butoxy-ethoxy)-phenyl]-acetic acid. HRMS : Observed mass of C24H26C1IN304+ (m+H+): 582.0655 ; Calculated mass: 582.0651. Example 120 (S) Good (2-Ga-4-iodo-phenyl)-2-{(R)-4-[4-(2-hydroxy-ethoxyphenyl]-2,5-side oxygen Base-mouth rice σ sitting bite _1_kib 3 -methyl-butylamine

制备 was prepared by the same method as described in Example 119 except that (R)-t-butoxycarbonylamino-{4-[2-(tetrahydro-pyran-2-yloxy) was used. ) _ ethoxy] phenyl}-acetic acid instead of (R)-t-butoxycarbonylamino-(4-cyclopropylmethoxy-phenyl)-acetic acid. Preparation of (R)-t-butoxy-ylamino-{4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl-acetic acid as described in Example 48 . HRMS : Observed mass of C22H24C1IN305+ (M+H+) : 572 〇 433 ; Calculated mass: 572,0444. Example 121 (S) Good (2-chloro-4-E-phenyl)-2-{(R)-4_[4-(2-methoxy-ethoxy)phenyl]-2'5- «One side oxy rice spit. Dec-1-yl}-3-methyl-butanamine

Ο Ι 28748.doc -128- 200848028 was prepared by the same method as described in Example 119 except that w-t-butoxyamino-[4-(2-methoxy-ethoxy) was used. ()) phenyl]_ 乙 S owing to replace (R) _ second butoxycarbonylamino group _ ('cyclopropyl methoxy-phenyl l acetic acid. Prepared as described in Example 80 (R) _ Third butoxycarbonylamino-[4-(2.methoxy-ethoxy)-phenyl]-acetic acid. HRMS : Observed mass of C23H26C1IN305 + (Μ+ΙΓ) : 586 〇586 ; 586.0600. Example 122 (S)-iV-(2-chloroiodo-phenyl)-2_{(κ)_4_[4_((Ιι)_2,3_dihydroxy-propoxy)-phenyl]-2, 5-tertiary oxy-imidazole pyridine 丨 基 基 } _ _ _ _ _ _ _ 醯 醯 醯

制备 Prepared by the same method as described in Example 3, except that (1) in the case of ν, use 2 - motholine to replace 4-dihydro-2-aniline, (Π) used in step (1) S) 2 - tert-butoxycarbonylamino-3-mercapto-butyric acid substitution (§ '3S) 2 - dibutoxyaminoamino 3 phenyl - butyric acid and (丨丨丨In step 2, (R)-t-butoxycarbonylamino-[4-((S)-2,2-dimercapto-[L3]-oxol-4-ylnonyloxybenzene is used. Substituting for the replacement of (R)-t-butoxycarbamoylamino-[4-(2-t-butoxy-ethoxy)-phenyl]-acetic acid. Prepared as described in Example 114 And using (R)-t-butoxycarbonylamino-[4_((s)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl ]_acetic acid. HRMS: observed mass of C23H25ClIN3Na06+ (M+Na+): 624.0367; 128748.doc -129- 200848028 Calculated mass: 624.0369. Example 123 (SHH2-chloro-4 winter phenyl)_2_{(κ)·4· [4_((8)_2,3_yl)-phenyl]-2,5-di-oxy-imidazolidinyl]-yl}_3-mercaptodihydroxy-propan-butylamine

ΟΗ r ι was prepared by the same method as described in Example 3 except that (1) 2-chloro-4-iodoaniline was used instead of 4-bromo-2-chloroaniline in step 1, (Η) in step 1. Use of (S)-2-tert-butoxycarbonylamino-3-3-methyl-butyric acid instead of (28,3 8)-2_second butoxycarbonylamino-3-phenyl-butyric acid And (丨丨丨) used in step 2 (R)-fluorenyldibutoxyamino]['((r)·, ^ dimethyl-[L3] dioxolane _4·yl Methoxy)-phenyl]-acetic acid replaces (R)-t-butoxyaminoamino-[4-(2-t-butoxy-ethoxy)-phenyl-p-acetic acid. (R)-Tertibutoxycarbonylamino-[4-((R)-2,2-dimethyl-[1,3]dioxolane-4- was prepared as described in Example 116. Methoxy)-phenyl]-acetic acid. HRMS: observed mass of C23H26C1IN306+ (M+H+): 602.0541; calculated mass: 602.0550. Example 124 (S)-A^(2-chloro-4-iodo-phenyl)_2-{(R)-4_(2,3-dihydro-benzo[1,4]dioxane-6- -2,5-di-oxy-imidazolidin-1-yl]-3-indolyl-butanamine

128748.doc -130- 200848028 was prepared by the same method as described in Example 11 9 except that (R)-t-butoxycarbonylaminodihydro-benzodioxan-6- (-)-tert-butoxycarbonylamino-(4-cyclopropylmethoxy-phenyl)-acetic acid. (R)-Tertibutoxyamino-(2,3-dihydro-benzo[1,4]dioxohex-6-ylacetic acid was prepared as described in Example 29. HRMS: C22H22C1IN305+ Observation mass (M+H+): 570·〇277; calculated mass: 570.0287. Example 125 (S)-7V-(2_gas_4_iodo-phenyl)-2-[(R)-4-(4 Dimethylamine decanoylmethoxy-phenyl)-2,5-di-oxy-imidazolidin-1-yl]-3-methyl-butylamine

Prepared by the same method as described in Example 9, except for the use of (R)-fluorenyldibutoxyamino-(4-dimethylamine-methoxycarbonyl-phenyl) Substituting - acetic acid substitution (Rl.sup.-butoxycarbonylamino-(4-cyclopropylmethoxy-phenyl)-acetic acid. By using (R)_third butoxide for use in Example i Preparation of (R)-Tertibutoxycarbonylamino-(4-dimethylamine-mercaptomethoxy-phenyl)_ by the same method as the carbonylaminoamino-4-methoxyphenylglycine Acetic acid, with the exception of 2- gas-W. dimethyl-acetamide instead of iodopyrene HRMS: observed mass of C24H27C1IN405 + (M+H+): 613 〇7〇3; calculated mass: 613.0709. Example 126 128748.doc -131 - 200848028 (8)|(2_Chloro-4-indolyl)_2-{(11)-2,5-di- oxy-4-[4-(2- oxooxy -2·-pyrrolidin-1-yl-ethoxy)-phenyl]-imidazole pyridine-^ kibhong methyl-butanamine

0 was prepared by the same method as described in Example 119 except that (R)-t-butoxycarbonylamino-[4-(2-o-oxy-2-indoleridin-1-) was used. (E)-Tertibutoxycarbonylamino-(4-cyclopropylmethoxy-phenyl)-acetic acid is replaced by benzyl-ethoxy)-phenyl]acetic acid. Preparation of (R)-dibutyloxyamino-amino group by the same procedure as in Example 1 for the preparation of (R)-t-butoxycarbonylamino-4-methoxyphenylglycine [4-(2-Sideoxy-2-°Pilo-1-yl-ethoxy)-benyl]-acetic acid', except for the use of 2-gas-1-u piroxicam-1 Base-B_ instead of methyl iodide. HRMS : Observed mass of C26H29ClIN4 〇5 + (Μ+η+) : 639.0864 ; Calculated mass: 639.0866. Example 127 (S)-2-[(R)-4-(4-{[bis-(2-hydroxy-ethyl)-aminecarboxylidene]-methoxy bromyl)-2,5_2 Oxyloxy-imidazolidine-1-yl]gas-4-iodo-phenyl)-3-methyl-butyric acid amine

128748.doc -132- 200848028 was prepared by the same method as described in Example 11 9 except that (R)-[4_(2-{bis-[2-(t-butyl-dimethyl)) was used. -石夕烧氧)_Ethyl]-aminophenylethyloxy)-phenyl]-tert-butoxycarbonylamino-acetic acid instead of (R)_t-butoxycarbonylamino-( 4-cyclopropylmethoxy-phenyl)-acetic acid. The third butyl-dimethyl-decyloxy)-ethyl]-aminophenylethyloxy)-phenyl]-tert-butoxycarbonylamino-acetic acid was prepared as described in Example 62. HRMS : Observed mass of C26H30ClIN4NaO7+ (M+Na+): 695.0739 ; Calculated mass: 695.0740. Example 128 (2S,3S)-2-{(R)_4_[4-(2-m-ylethoxy)-phenyl]-2,5-di-oxy-imidazolidin-1-yl}- 3-methyl-pentanoic acid (2-chloro-4-iodo-phenyl)-decylamine

Prepared by the same method as described in Example 3, except that in step 1, 2-oxo-iodoaniline was used instead of 4-bromo-2-aniline and (2S,3S)-2-third butyl was used. Oxycarbonylamino-3-methyl-pentanoic acid replaces (2S,3S)-2-t-butoxycarbonylamino-3-phenyl-butyric acid. HRMS : Observed mass of C23H26C1IN305 + (M+IT) : 586.0603 ; Calculated mass: 586.0600. Example 129 (28,38)-2-[(11)-4-(2,3-dihydro-benzo[1,4]dioxohex-6-yl)_2,5-128748.doc-133 - 200848028 Bi-oxy-imidazolidine-1-yl]-3-methyl-pentanoic acid (2-Ga-4-iodo-phenyl)-decylamine

Prepared by the same method as described in Example 128 except that (R)-t-butoxycarbonylamino-(2,3-dihydro-benzo[1,4]dioxane was used. -6-yl)-acetic acid replaces (r)-t-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid. (R)-Tertibutoxycarbonylamino-(2,3-dihydro-benzo[M]dioxane-6-yl)-acetic acid was prepared as described in Example 29. HRMS · Observed mass of C23H24CIIN3O5 (M+H+): 584.0438 ; Calculated quality $ . 584.0444. Example 130 (2S,3R)-iV-(2-Ga-4-iodo-phenyl)-2-{(R)_4_[4_(2-hydroxy-ethoxy)-phenyl]-2,5-di Sideoxy-imidazolidin-1-ylbu 3_methoxy-butanamine

, except that in step 2 · chloro-4-disaniline and using -methyl-butyric acid instead of (S)-2-, the same procedure as described in Example 72 was used to prepare 2-fluoro in step 1. -4-iodoaniline instead of 2•chloro*(2S,3R)-2-tert-butoxycarbonylamino-3_methoxyphene dibutoxy-carbylamino-3_σ-seiphen-2-yl_ Propylene 128128748.doc -134- 200848028 LC-MS : Observed mass of C22H24CllN3〇6+ (M+H+) : 588 ;Computational mass: 5 8 8 〇Example 131 (2S,3S)-2-{(R) -4-[4-(2-methoxy-ethoxy)-phenyl]-2,5-di-oxy-imidazolidin-1-yl 3-methyl-pentanoic acid (2_gas_ 4. Iodine-phenyl)-decylamine

Prepared by the same method as described in Example 3, except that (1) 2-chloro-4-iodoaniline was used instead of 4-bromo-2-aniline in step 1, and (Π) was used in step 1 ( 2S,3S)-2-Tertoxycarbonylamino-3-methyl-pentanoic acid replaces (2S,3S)-2-tert-butoxyamino-3-phenyl-butyric acid and (R) in step 2 using (R)-t-butoxymethylamino-[4-(2-methoxy-ethoxy)-phenyl]-acetic acid instead of (R)-third Oxycarbonylamino-[4_(2_t-butoxy-ethoxy)-phenyl]-acetic acid. (r)-Tertibutoxycarbonylamino-[4-(2-methoxy-ethoxy)-phenyl]-acetic acid was prepared as described in Example 80. HRMS : Observed mass of C24H28ClIN3〇5 + (Μ+Η+) : 6〇〇 〇758 ; Calculated mass: 600.0757. Example 132 (2S, 3R) is good (2' chloro-4-indolyl)-2-{(R)-4-[4-((R)-2,3-dihydroxy-propoxy)- Phenyl]-2,5-di-oxy-imidazolidinyl-3-methoxy-butanamine 128748.doc -135- 200848028

Prepared by the same method as described in Example 114 except that (1) was replaced with (2S,3R)-2-t-butoxycarbonylamino-3-methoxy-butyric acid (2S,3S) -2-t-butoxycarbonylamino-3-3-phenyl-butyric acid. LC-MS · Observed mass of C23H26C1IN307+ (M+H+): 61 8 ; Calculated mass: 618. Example 133 (2S,3S)-iV-(4-iodo-2-methyl-phenyl)-2-[(R)-4-(4-decyloxy-phenyl)-2,5-di-side Oxy-imidazolium-hydrazino-yl]-3-phenyl-butanamine

Prepared by the same procedure as described in Example 1, except that 4-iodo-2-methyl-phenylamine was used in place of 4-bromoaniline in Step 2. HRMS : Observed mass of C27H27IN3〇4+ (M+H+) : 584.1042 ; Calculated Quality: 584.1041. Example 134 (2S,3S)-2-{(R)-4-[4-(2-hydroxy-ethoxy)-phenyl]_2,5·di-oxy-m-pyridin-1-yl 7V-(4-iodo-2-methyl-phenyl)-3-phenyl-butanamine-136-128748.doc 200848028

By using the 4-iodo-2-methylaniline instead of 2-iodo-2-methylaniline as described in Example 48, the mass of observation (μ+η+): 6ΐ4 ι(1) Quality: 614.1147. #

Example 135 (2s,3S)m2-indolyl-phenyl)_2-{called 4_[4♦methoxy-ethoxy)-phenyl]-2,5-di- oxy--sweet base _Butylamine

Prepared by the same method as described in Example 48 except that (1) in step 2, 4-iodo-2-methylaniline was used in place of 2-fluoro-iodobenzamine and (ii) using (R)· Tributoxycarbonylamino-[4-(2-decyloxy-ethoxy)-phenyl]-acetic acid instead of (R)-t-butoxy-ylamino-{4-[2-( Tetrahydro-pyr. Nan_2-yloxy)-ethoxy]-phenyl-acetic acid. (r)-Tertibutoxycarbonylamino-[4-(2-methoxy-ethoxy)-phenyl]-acetic acid was prepared as described in Example 80. HRMS ·· C29H3iIN3〇5 + observation quality (M+H+): 628.1 293 ; calculation mass · · 628.1303. Example 136 128748.doc -137- 200848028 (10),38)4(4Winter 2_methyl-phenyl)_2_((R)_4_{4_dmethoxy-ethylidyl)ethoxy]-phenyl}- 2,5-di-side oxy+sodium pyridinium

I.. was prepared by the same method as described in Example 48 except that (1) using 4-iodo-2-methylaniline instead of 2-fluoro-iodoaniline and (η) using (R)- Third butoxycarbonylamino group [4·(2·{2_methoxy-ethoxyethoxy)phenyl]-acetic acid instead of (R)-t-butoxycarbonylamino group _ {4_[2_(tetrahydro-bran-2-yloxy)-ethoxy]-phenyl-acetic acid. (R)-Tertibutoxycarbonylamino-[4_(2_{2_methoxy-ethoxyethoxy)-phenyl]-acetic acid was prepared as described in Example 4$, except for Instead of 2 _{2 - desert-ethoxy)-tetrahydropyran, 1-{2-bromo-ethoxy)-2-methoxy-ethene was used. HRMS : observed mass of C31H35IN306+ (M+H+): 672.1556 ; Calculated mass: 672.1565. Example 137 (2S,3S)-7V-(4-ethynyl-phenyl)-2-[(R)-4-(4-decyloxy-phenyl)-2,5-di-oxy-imidazole Pyridin-1-yl]-3-phenyl-butanamine

128748.doc -138- 200848028 was prepared by the same method as described in Example 1, except that (1) 4 - ethyl phenyl aniline was used instead of 4- aniline in step 2, (ii) in step 4 (3-Dimethylamino-propyl)-ethyl-carbodiimide hydrochloride is used as a coupling reagent instead of hexafluoro-acid &lt;9-benzotrixen-1-yl-TV, TV, V , V-tetramethyl is recorded and (iii) the third butoxy protecting group is decomposed using formic acid as described below in steps 3 and 5. Preparation of (2S,3S)-2-amino-jV-(4-ethylfastyl-phenyl)-3-phenyl-butyric acid amine: [(1S,2S)-1-(4-ethynyl- A suspension of phenylaminomethane)-2-phenyl-propyl]-amino decanoic acid tert-butyl ester (300 mg, 0·79 mmol) in methanol (5 mL) was heated to 50 ° C It lasted 1 hour. The reaction was concentrated in EtOAc (EtOAc)EtOAc. The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and evaporated in vacuo to give (2S,3S)-2-amino-2-(4-ethynyl-phenyl) -3-Phenyl-butanamine (214 mg, 92%). HRMS : C28H25N3Na04 ten observation mass (M+Na+): 490.173 1 ; Calculated mass: 490.1737. Example 138 (S)-7V-(4-ethynyl-2-fluoro-phenyl)-2-{(R)-4-[4-(2-methoxy-ethoxy)-benyl]- 2,5-di-oxyl-flavor 0 sit-n-yl}-3-phenyl-propan-8 amine

128748.doc -139- 200848028 was prepared by the same method as described in Example 140 except that (2S)-2-di-dibutoxy&gt;carbonylamino-3-phenyl-propionic acid was used. Instead of (2s dibutoxylk-amino-3-phenyl-butyric acid and using (r)-t-butoxycarboylamino-[4-(2-methoxy-ethoxy) 】Phenyl]-acetic acid instead of (r)_second butoxy^ anoylamino-{4-[2-(tetrahydro-l-butan-2-yloxy)-ethoxy]-phenyl Acetic acid. Preparation of (R)-t-butoxycarbonylamino-[4-(2-methoxy-ethoxy)-phenyl]-acetic acid as described in Example 80. HRMS: observed mass of C29H27FN305+ (M+H+): 516.1932; Calculated mass: 516.1929. Example 139 (2S,3S)_2-((R)-2,5-di- oxy-4-phenyl miso 嗤α定小基)_τν_(4 _ethynyl-2-fluoro-phenyl)_3_phenyl-butanamine

Prepared by the same method as described in Example 140, except that (R) dibutoxyamino-yl-acetic acid was used instead of (R)-t-butoxydecylamino-{ 4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy> phenyl}•acetic acid. HRMS : observed mass of c27H22FN3Na03+ (M+Na+): 478.1529 ; Calculated mass: 478.1537. Example 140 ()V (4·B-Butyl-2-fluoro-phenyl)-2-{(R)_4 - [4-(2-propionyl-ethoxy)-128748.doc-140- 200848028 Benzene -2,5-di-oxy-imidazole pyridine-:[_ kib 3-styl-butyramine, isomer 1

Prepared by the same method as described in Example 48, except that (1) after step 3 and before step 4, (2S, 3S)_2_fet iV (2-fluoro-) 4-(Indolyl-benzamine)-3-phenyl-butanamine is converted to (2s,3S)-2_aminofluoro-4-trimethyldecylethynyl-phenyl)-3-phenyl-butanamine And (11) after the purification was started in step 6, the product was subjected to a palmitic HPLC separation as described below. The trimethyldecylalkyl group introduced in step 3 is subsequently removed during the synthesis step 5 while removing the third butoxycarbonyl protecting group. Preparation of (2S,3S)-2-amino-τν-(4-ethynyl-2-fluoro-phenyl)-3-phenyl-butanamine: (2S,3S)-2-Amino-indole - (2 ϋ moth-phenyl)-3-phenyl-butanamine (1.00 g, 2.51 mmol) in triethylamine (1 5 mL, 1 〇 8 mm 〇 1) was fully degassed with argon, added Bis-di- gas triphenylphosphine palladium (11) (2〇3, 〇·〇 5 mmol) 'Addition of molybdenum (9 8 , 〇〇 5 mm.) and trimethyl decyl acetylene (277 Mg, 2.77 mmol) and the mixture was stirred under argon at ambient temperature for 3 hours. Additional triethylamine 〇.5 mL, 1 〇 8 mmol) was added to form a stirrable reaction mixture and stirring was continued for an additional hour. The reaction mixture was diluted with diethyl ether and a small amount of diatomaceous earth was added, followed by filtration through alumina, and the stone bath was dissolved in B_(4×20 mL) and the combined organic filtrate was in the vacuum of 128748.doc -141 - 200848028 concentrate. The obtained green oil was dissolved in a small amount of diethyl ether and diluted with hexane(0 mL) to initiate crystallization. The product was isolated by filtration, washed with hexanes and dried in vacuo to afford (2S,3S)-2-amino-#-(2-fluoro-4-trimethyldecylalkylethynyl) as a gray solid. _Phenyl)_3_phenyl-butanamine (610 mg, 66%). The second batch of product (1 68 mg, 18.8%) was obtained by reprocessing the mother liquor from the initial crystallization. HRMS: The observation quality of the 匕 洲 洲 洲 : 369 1793 ; The calculated quality: 369.1793. Separation of palmar HPLC: (3S)_'(4-ethynyl-2-fluoro-phenyl)_2-{(11)_4-[4-(2-hydroxy-ethoxy)-phenyl]-2 ,5·di-oxy-imidazolidinyl 3&gt;_Phenyl-butanamine sample (22 mg, 0.43 mmol) using a 2.0 cm x 25 cm Daicel OD column for palmitic hplC at 1:1 v /v Hexane in absolute ethanol was purified by dissolving in 5 ml per minute while UV detection was used at 26 〇nrn to monitor the presence of the product in the eluate. The first lysate was collected and concentrated in vacuo to give (3S)-7V-(4-ethynyl-2-fluoro-phenyl)-2-{(R)_4-[4-(2) -Hydroxyethyloxy)-phenyl]·2,5-di-oxy--oxazolidine-based group -3 -benyl-butanylamine isomer 1 (6 mg, 28%). HRMS : Observed mass of C29H27FN305+ (M+H+): 516.1926 ; Calculated mass · · 516.1929. Example 141 (3S)-7V-(4-Ethynyl-2-fluoro-phenyl)-2-{(R)-4-[4-(2-transylethoxy)-phenyl]-2, 5-tertiary oxy-imidazolidin-1-ylphenyl-butanamine, isomer 2 128748.doc -142- 200848028

Prepared by the same method as described in Example 140, except that the second lysate from the palm of the HPLC purification was collected and concentrated in vacuo to afford (3S)-TV- as a colorless solid. (4-ethynyl-2-fluoro-phenyl)-2-{(R)-4-[4-(2-trans-ethoxy-phenyl)-phenyl]-2,5·di-oxy-嗤 (Bite-2-ylpyr-3-phenyl-butanamine, isomer 2 (7 mg, 32%). HRMS: observed mass of C29h27fn3 〇5+ (M+H+): 516.1931 ; 516.1929. Example 142 (3S) Spring (4-ethynyl-2-fluoro-phenyl)-2-{(R)-4-[4-(2-methoxy-ethoxy) base]-2 ,5_ one side gas-based sit-n-1-yl}-3-phenyl-butylamine, isomer 1

Prepared by the same method as described in Example 140, except for the use of (Rl·t-butoxycarbonylamino-[4-(2-methoxy-ethoxy)-phenyl]-acetic acid Substituting (R)-t-butoxycarbonylamino-{4_[2-(tetrahydro-piperidin-2-yloxy)ethoxy]-phenyl-acetic acid. Prepared as described in Example 8 ( R)_Tertibutoxycarbonylamino-[4-(2-methoxy-ethoxylated phenyl;]•acetic acid. By 128748.doc -143 - 200848028 The final product was purified by gradient elution of 30 〇 / 〇 v / v in hexane. The first lysate was collected and concentrated in vacuo, followed by hexane (10 mL) from diethyl ether containing a small amount of methane. Precipitation in (1 mL). The precipitated solid was collected by filtration and dried to give (3S)-'(4-ethynyl-2-fluoro-phenyl)-2-{(R)_4_ as a colorless solid. [4_(2-methoxy-ethoxyl.phenyl)-2,5-di-oxy-imidazole pyridine 丨 基 3 3 phenyl-butanamine, isomer 1 (19% HRMS : observed mass of C30H28FN3NaO5 + (M+Na+): 552.1905 ; Calculated mass: 552.1905. Example 143 (3S)i-(4-ethynyl-2- ·Phenyl)_2-{(κ)_4_[4_(2_methoxy-ethoxyphenyl)-2,5-di-oxy-imidazole pyridine-hydrazinyl phenyl-butanamine , isomer 2 &quot;

Prepared by the same procedure as described in Example 142, except that the second eluted product from the final reaction product was purified by chromatography. The second, contained product was collected and concentrated in vacuo, then hexane (1 mL) was used to dissolve from diethyl ether (1 mL) containing oxime I. The solid was collected by filtration and dried to give (an ethynylfluoro-phenyl)-2-{(Κ)-4-[4-(2-methoxy-ethoxy y) as a colorless solid. Phenyl]-2,5-di-oxy-imidazolidine-1-yl}-3-phenyl-butanamine, isomer 2%). 128748.doc -144- 200848028 HRMS : Observed mass of C30H28FN3NaO5+ (M+Na+): 552.1906 ; Calculated mass: 552.1905. Example 144 (S)-iV-(4-ethynyl-2-fluoro-phenyl)-2-((R)-4-{4-[2-(2-decyloxyethoxy)-B Oxy]-phenyl b 2,5-di-oxy-imidazolidin-1-yl)-3-phenyl-butanamine

Prepared by the same method as described in Example 140 except that (R)-di-dibutoxyamino-{4-[2-(2-methoxy-ethoxy)- Ethyloxy]-phenyl}-acetic acid instead of (R)-t-butoxycarbonylamino-{4-[2-(tetrahydro-l-butan-2-yloxy)-ethoxy]-benzene Base}-acetic acid. (R)-Tertibutoxycarbonylamino-{4-[2-(2-methoxy-ethoxy)-ethoxy]-phenyl}-acetic acid was prepared as described in Example 48, but The exception is the use of 1_(2_bromo-ethoxy)_2_methoxy-ethene instead of 2-(2-di-ethoxy)-tetrahydropyran. HRMS : C32H32FN3Na (V observed mass (M+Na+): 596.2168; Calculated mass: 596.2167. Example 145 (2S?3S)-2-{(R)-255- One-side oxy-4-[4-(2 - sideoxyl ratio slightly biti-ethoxy)-phenyl]-salt, 1-ylethynyl-2-I-phenyl)-3-phenyl-butylamine 128748.doc -145- 200848028

制备 Prepared by the same method as described in Example 140 except that (R)-t-butoxycarbonylamino-[4-(2-o-oxy-2·b-pyrrolidine-i-) was used. (-)-tert-butoxycarbonylamino-{4_[2_(tetrahydro-piperidin-2-yloxy)-ethoxy]-phenyl} -Acetic acid. Preparation of (R)-t-butoxycarbonylamino-[[4-(2.sub.oxy-2-indole-l-yl-ethoxy)-benzene as described in Example 126 HRMS: observed mass of c33H32FN405+ (M+H+): 583.2352; calculated mass: 583.2351. Example 146 (S) TV- (2- gas-4-ethyl-based-phenyl)-2-{4 -[4-(2-trans)-ethoxy)-phenyl]-2,5-di-oxy-imidazolium-fluorenyl-yl}-phenyl-propanamide, isomer 1

Prepared starting from (S)-2-amino-(2-carb-4-iodo-phenyl)-3-phenyl-propionamide as described below. Amino-(2-chloro-4-iodo-phenyl)-3-phenyl-propanamide was prepared by the same procedure as described in Step 1 of Example 3, except that 2-chloro-4- Iodine-aniline replaces 4_bromo-2-chloro-aniline and replaces (S,S)-2-third butoxide with (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid Carbocarbonylamine 128748.doc -146- 200848028 base-3-phenyl-butyric acid. Step 2: (S)-2-Amino-(2-chloro-4-iodo-phenyl)-3-phenyl-propanamide (980 mg, 2.44 mmol), bis-dichlorotriphenylphosphine | Bar (19.8 mg, 0.0489 mmol) and cuprous bismuth (9.5 mg, 0.049 mmol) were added to the dry flask. Trimethylsulfonylalkylacetylene (269.7 mg, 2.69 mmol) in anhydrous triethylamine (1·46 mL) was added to this mixture. After 30 minutes, anhydrous dioxane (1 mL) was added. After 3 hours, additional bis-diqitriphenylphosphine Ib (40 mg, 0.099 mmol) and cuprous copper (20 mg, 0.099 mmol) were added. After 1 hour, the reaction mixture was diluted with a 1:1 v/v mixture of diethyl ether/dichloromethane and passed through a bed of Shixi gum and then the gelatin was tested at 2:3 v/v. The mixture of decane is dissolved. The eluate was concentrated in vacuo and the crude residue was purified eluting with EtOAc EtOAc EtOAc. The mixed product-containing fractions were concentrated to give (S)-2-amino-#-(2-carb-4-trimethyldecylethynyl-phenyl)-3-phenyl as a white solid. - acrylamide (820 mg, 90% yield). Step 3: (s)-2-Aminochloro-4-trimethyldecylalkyl acetylene was used in the same manner as described in Step 4 of Example 1. _-phenyl)_3_phenyl-propionamide and (R)-second butoxycarbonylamino group _{4_[2_(tetrahydro-piperidin-2-yloxy)-ethoxy]- Phenylacetic acid (prepared as described in Example 48) was coupled to give ((SH(8) small (2-aze-4-trimethyldecylalkylethynylphenylamine)-phenyl-ethylamine Methyl hydrazide]·{4_[2_(tetrahydro-piperidin-2-yloxy&gt; ethoxy]-phenyl-methyl)-carbamic acid tert-butyl ester. Step 4 ··((SH(8) heart Trimethyl sulphur-based ethyl bromide-phenylaminocarboxylic acid)-2-phenyl-ethylamine-methyl sulfonyl b. [4 cases of tetrachloro-branol-2-yloxy 128748.doc -147- 200848028) -Ethoxy]-phenyl-methyl)-tert-formic acid tert-butyl ester (491 mg, 0.656 mmol) was dissolved in citric acid (71 mL) and heated at 4 Torr for 3 Torr. Incubation was carried out for a period of 3 hours between 50 and 551. The reaction mixture was concentrated in vacuo and the residue was taken crystalljjjjjjjjjj The combined organic extracts were dried over sodium sulfate, EtOAc (EtOAc m. The residue of the product was concentrated to give a white residue. EtOAc m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m 2-[4-(2-Hydroxy-ethoxy)-phenyl]-acetamidochloro-4-(3-o-oxy-propan-1-yl)-phenyl]-phenyl - Propylamine (240 mg, 70%). Step 5: Cyclization using diphosgene was carried out in the same manner as described in Step 6 of Example 1 except that after treatment, the crude material (25 〇) Mg) dissolved in methanol (11.3 mL), cooled in an ice-bath and treated with sodium borohydride (123 mg, 3.28 mmol). After 15 min, the reaction was treated with 15 n aqueous potassium hydrogen sulfate and acetic acid. B The ester was extracted (3 x 50 mL). The combined organic extracts were washed with EtOAc EtOAc EtOAc EtOAc. A crude mixture of the isomers. Step 6: The crude mixture of the diastereomers was purified by chromatography using a Daicei OD column eluting with methanol in 50% v/vm. The faster-flowing component was concentrated in vacuo and dissolved in ethyl acetate (100 mL). The organic solution was washed with 5% w/v sodium bicarbonate aqueous solution 128748.doc-148-200848028 (3x50 mL) and The water was then combined and back extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried over sodium sulfate and concentrated to give (S)-7V-(2- s.sup.4- ethynyl-phenyl) s. Stupid base-2,5-di-oxy-imidazolidin-1-yl-3-phenyl-propanamide, isomer 1 (64 mg, 25.5% yield). HRMS : observed mass of C28H25CIN3O5 (M+H+) : 5 1 8· 1477 ; ancient ten calculated mass: 518.1477. Example 147

-2,5-di-oxy-imidazolidin-1-yl b-phenyl-propionamide, isomer 2

By the same reaction as described in Example 146 and in Step 6, the flow was slower--(2-gas·4·B-yl-phenyl 2,5-di-oxy-imidazole-1 - base mg, 18.5% yield). HRMS : C28H25C1N305+ advises you

Stupid base - • succinyl-ethoxy)-phenyl]-propionamide, isomer 2 (observed mass of 42 (M+ mine) 518.1472; tf calculated mass: 518.1477. Example 148

))-phenyl]-2,5-di- oxy-methane-sodium ΚΚ)-'[4-(2-methoxy-ethoxyh-h-bu- 3-phenyl-propanamine 128748.doc • 149 - 200848028

'O~〇s

Os was prepared by the same method as described in Example i46, except that (1) (R)-Tertioxymethylamino*(2-methoxy-ethylphenyl) was used in Step 3. Acetic acid replaces (R)_t-butoxycarbonylamino-{4_[2_(tetrahydrohenanyloxy)-ethoxyl-phenyl}-acetic acid. Preparation as described in Example 80 f Second butoxycarbonylamino-[4-(2-methoxy-ethoxy)-phenyl]-acetic acid '(ii) is not present in the step 5 after the treatment with diphosgene and Therefore, it is not necessary to treat with sodium borohydride, and (iii) no diastereomers are observed after step 5 and thus it is not necessary to separate the diastereomers by supercritical fluid chromatography (in Example 146). Step 6) HRMS: Observed mass of C29H27ClN3 〇5+ (M+H+): 532.1634; Calculated mass: 532.1634. Example 149 Ο (28,38)^-(2-Gas-4-ethynyl-phenyl)- 2-{()-4-(4-(2-hydroxy-ethoxyphenyl)-2,5-di-oxy-imidazolidin-1-yl-3-phenyl-butanamine)

O〇s

OH was prepared by the same method as described in Example 146 except that (2S,3S)-2-t-butoxycarbonylamino-3-phenyl-butyric acid was used instead of (s)_2-di Dibutoxyweiylamino-3-phenyl-propionic acid. 128748.doc -150- 200848028 HRMS : Observed mass of C29H27C1N305+ (M+H+): 532.1637 ; Calculated quality: 532.1634. Example 150 (28,3 8)-7ν»(2-Ga-4-ethylidyl-phenyl)-2-{(R)-4-[4-(2-methoxy-ethoxy)- Phenyl]-2,5-di-oxy-imidazolidin-1-yl-3-phenyl-butanamine

Prepared by the same method as described in Example 149, except that (R)-t-butoxycarbonylamino-[4-(2-methoxy-ethoxy)-phenyl]- Acetic acid replaces (R)-t-butoxycarbonylamino-{4_[2-(tetrahydro-piperidin-2-yloxy)-ethoxyphenylphenylacetic acid. The third butoxycarbonylamino-[4-(2-methoxy-ethoxy)-phenyl]-acetic acid was prepared as described in Example 8A. HRMS : Observed mass of C30H29ClN3O5+ (m+h+) : 546 1785 · Leaf Calculated mass: 546.1790. Example 151 (2S,3S)-iV-(2't^4_ethynyl-phenyl)-2_((κ)_4_{'[2_(2_methoxy-ethoxy)-ethoxy]-benzene 2,5-di-side oxy-imidazolium hydrazide-yl)-3_phenylbutyramine

128748.doc -151 - 200848028 was prepared by the same method as described in Example 15, except that (R)-t-butoxy-carbylamino]4_[2-(2-methoxy) was used. _Ethoxy)-ethoxyl-1 phenylacetic acid instead of (R)-t-butoxymethylamino-[4f(2-methoxy-ethoxy)-phenyl]-acetic acid. (R)-Tertibutoxycarbonylamino-{4-[2-(2-methoxy-ethoxy)-ethoxy]-phenyl-acetic acid was prepared as described in Example 48, with the exception To replace 2-(2-di-ethoxy)-tetrahydropyran with 1-(2-bromo-ethoxy)-2-methoxy-ethane. HRMS : observed mass of C32H33C1N306+ (m+H+): 590.2053; ancient ten' calculated mass: 590.2053. Example 152 (S)-7V-(2-Ga-4-ethylidyl-phenyl)-2-{(R)-4-[4-(2-decyloxy-ethoxy)-phenyl] -2,5-di-oxy-imidazolidin-1-yl}-3-methyl-butanamine

Prepared by the same method as described in Example 150 except that (S)-2-tert-butoxycarbonylamino-3-methyl-butyric acid was used instead of (2S,3S)-2- Tributoxycarbonylamino-3-phenyl-butyric acid. HRMS : Observed mass of C25H26ClN3Na05+ (M+Na+): 506.1455; Calculated mass: 506.1453. Example 153 (2S,3S)-2-{(R)-4-[4-(2-methoxy-ethoxy)-phenyl]-2,5-di- oxy--scented -i_kib 3 -methyl-decanoic acid (2-air-4-ethylidene-yl)-acid amine 128748.doc -152- 200848028

ο ο—

Prepared by the same method as described in Example 150 except that (2S,3S)-2-t-butoxycarbonylamino-3-methyl-pentanoic acid was used instead of (2S,3S)-2. - Third butoxycarbonylaminophenyl butyric acid. HRMS : Observed mass of C26H28ClN3Na05+ (M+Na+): 520.1612 ; Calculated mass: 520.1609. Example 154 (2S,3S)-iV-(4-ethynyl-2-indenyl-phenyl)-2-{(R)-4-[4-(2-methoxy-ethoxy)-styl -2,5·di-oxy-imidazolidin-1-yl b-phenyl-butanamine

〇 〇 - Prepared by the same method as described in Example 150 except that 2-iodo-4-iodomethylaniline was replaced with iodine-2-methylaniline. HRMS : Observed mass of C31H31N3Na05+ (M+Na+): 548.2154 ; Calculated mass · · 548.2156. Example 155 (2S,3S)-7V_(4-ethynyl-2-methyl-phenylmethoxy-ethoxy)-ethoxy]-phenyl b 2,5-di-oxy-imidazole ―卜基)”-Phenyl-butanamine 128748.doc -153- 200848028

It was prepared by the same method as described in Example 151 except that 4-A.2.methylaniline was used instead of 2. HRMS · Observed mass of C33H35N3Na〇6 (M+Na+) : 592·2411 ; Calculated mass: 592.2418. Example 156 (28,3 8)-, (4_cyclopropyl-phenyl)_2_{(11)-4-[4&lt;2-hydroxy-ethoxy>phenyl]-2,5-two side Oxy-imidazolium-oxime-kib phenyl-butanamine

Prepared by the same procedure as described in Example 48 except that 4-cyclopropyl-phenylamine was used instead of 2-fluoro-4-iodoaniline. HRMS : Observed mass of C3〇H32N305+ (Μ+Η+) : 5 14.2333 ; Calculation Quality: 514.2337. HRMS ·· C30H31N3NaO5+ observation mass (M+Na+): 536.2153 ; Calculated mass: 536.2156. Example 157 (8)-D-(4-cyclopropyl-2-fluoro-phenyl)-3-(4-fluoro-phenyl)_2-{()-4-[4-(2-amino-) Ethoxy)-phenyl]-2,5-di- oxy, imi. sit.定-1 _ propyl propylamine 128748.doc -154- 200848028

Prepared by the same method as described in Example 160 except that (R)-second butoxycarbonylamino group _{Heart [2_(tetrahydro-piperidin-2-yloxy)) Oxy]-phenyl}-acetic acid replaces (R)-t-butoxycarbonylamino-[4_(2•hydroxyl^^-methyl-ethoxy)-benzyl]-acetic acid. (R)-Secondoxycarbonylamino-{4_[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-acetic acid was prepared as described in Example 48. HRMS: Observed mass of C29H28F2N305+ (M+H+): 536.1986; Calculated mass: 536.1992. Example 158 (S) I(4_cyclopropyl-2-fluoro-phenyl)-2-{(called 4-[4-((phantom-2,3-dihydroxy-propoxy)-phenyl] -2,5-di-oxy-misazolidin-1-yl-3-(4-fluoro-phenyl)-propanamide

Prepared by the same method as described in Example 160, except that (R) di-butoxy-carbylamino-[4-((R)-2,2-dimethyl-[!, 3] Dioxindole-4-ylmethoxyoxyphenylacetic acid instead of (R)-t-butoxycarbonylamino[4-(2-.yl-methyl-ethoxy)-benzene • Acetic acid. Prepared and used as described in Example 11 4 128748.doc -155- 200848028 (R)-Tertibutoxycarbonylamino-[4_((κ)-2, dimethyl-[1 , 3] dioxol-4-ylmethoxy)-phenyl]-acetic acid. HRMS · observed mass of c30H30F2N3O6+ (Μ+Η+) : 566.2099 ; calculated mass: 566.2097. Example 159 (S)-^( 4-cyclopropyl-2-fluoro-phenyldihydroxy-propoxy)-phenyl]-2,5-di-oxy-mi-waw _1_yl}_3_(4-fluoro-phenyl) _ acrylamide

f was prepared by the same method as described in Example 160 except that (R)-t-butoxycarbonylamino-[4-((s)-2,2-dimethyl-[1] was used. , 3]dioxolan-4-ylmethoxy)-phenyl]-acetic acid instead of (R)-t-butoxycarbonylamino-[4-((R)-2,2-didecyl) -[1,3]dioxolan-4-yloxy)phenyl]-acetic acid. Prepared and used as described in Example 116 and using (R)-t-butoxycarbonylamino-[4-((S)-2,2-dimethyl-[1,3]dioxolane_4_ Methoxy)-phenyl]-acetic acid. HRMS : Observed mass of C30H29F2N3NaO6+ (M+Na+) : 588 1912 ; Calculated mass: 588.1916. Example 160 (S)-iV-(4-cyclopropyl-2-fluoro-phenyl)-3-(4-fluoro-phenyl)_2-{(r)-4-[4-(2-128748. Doc -156- 200848028 hydroxy-1-hydroxymethyl-ethoxy)-styl]_2,5-di-oxyl-imidazolidinium_ι_yl}· propylamine 〇, Η

〇 Λλ (〇η〇Η

Prepared by the same method as described in Example 3, except that (1) Substituting (S)-2-t-butoxycarbonylamino-3_(4-fluoro-phenyl)-propionic acid in step 1 (2S,3S)-2_t-butoxycarbonylaminophenyl-butyric acid, (ii) after step 2 and before step 3 (SH1_(2•fluoro_4_iodo-phenylamine formazan) Conversion of tert-butyl 2-(4-fluoro-phenyl)ethylidenecarboxylate to (shi_(4-cyclopropyl-2-fluoro-phenylaminemethanyl)-2_(4 _Fluoro-phenyl)-ethyl]-carbamic acid tert-butyl ester (using the following conditions), (iii) in step 4, using (R)-t-butoxycarbonylamino-[4- (2-Hydroxy-1-hydroxymethyl-ethoxy) &lt;Phenylacetic acid (prepared as described below) in place of (R)-t-butoxycarbonylamino-{4-[2-(tetrahydro-) Piper-2-yloxy)-ethoxyphenyl phenylacetic acid, and (iv) will be included in (s) _ 2 during the step 6 by the same method as described in Example 4 -{2-Amino-2·[4-(2-hydroxy-1-hydroxyindolyl-ethoxy)-phenyl]-acetamidophenyl 7V_(4-cyclopropyl-2-fluoro-benzene Temporary protection of diol functional groups in the group -3_(4_fluoro-phenyl)-propionamide Preparation of (SMl-(4-cyclopropyl_2-fluoro-phenylaminecarbamyl)&gt;2_(4-fluoro-phenyl)-ethyl]-carbamic acid Butyl ester: Dipotassium carbonate (6.68 g, 3 1.5 mmol), tricyclohexylphosphine (〇·50 g, 128748.doc -157-200848028 1.8 mmol) and palladium acetate (〇·2〇g, 0.89) Ment) added to a mixture of toluene (40 mL) and water (2 mL) in a mixture of toluene (phenylamine-mercapto)-2-(4-fluoro-phenyl)-ethyl]-carbamic acid Butyl ester (45 g, 9. 〇mmol) and cyclopropyl tanning acid (1·〇g, ιι·7 mm〇1). The mixture was heated to 100 ° C for 3 hours, followed by the addition of tricyclohexyl Phosphine (〇, 25 g, 〇89 mmol) and palladium acetate (0·10 g, 0.45 mmol). Continued to reheat for 3 hours under TC (TC), followed by cyclopropyl-teric acid (〇·2 g, 2.33) Ment) and heated for a period of 3 hours at 100 ° C. The reaction mixture was diluted with ethyl acetate, washed with water (twice), brine (s), dried over sodium sulfate &lt; The residue was chromatographed with 9:1 v/v in hexanes by chromatography. Purification by dissolving to provide (S)-[l-(4-cyclopropyl_2-fluoro-phenylaminecarbamimidyl)-2-(4-fluoro-phenyl)-ethyl]amine as a colorless solid Tert-butyl carboxylic acid (2.0 g, 53%). LC-MS: observed mass of C23H27F2N203+: 417. Calculated mass: 417 ° Preparation of (R)-t-butoxycarbonylamino-[4-(2- Hydroxy-1-hydroxymethyl-ethoxy)-phenyl]-acetic acid: (1) According to the procedure of Shimizu, M. et al. (J. C/zem. C/2em. Comm (10) 1986, 867), 2-Benzyloxy-1-benzyloxyindenyl ethyl ester of 2,5-dichlorobenzenesulfonic acid was obtained from 1,3-bis-benzyloxy-propan-2-ol. (2) To (R)-Tertibutoxycarbonylamino-(4-hydroxy-phenyl)-acetic acid (10 g, 3.74 mmol) in anhydrous bromo, dimethyl decylamine (50 mL) Sodium hydride (60% suspension in mineral oil) (328 mg, 8.2 mmol) was added to the solution and the mixture was stirred at ambient temperature under dry argon for 15 min. Add 128748.doc -158- 200848028 2,5-Dichloro-benzenesulfonic acid 2-benzyloxy-1-benzyloxymethyl group dissolved in anhydrous TV, dimethyl decylamine (25 mL) Ethyl ester (2.2 g, 4.57 mmol), and the stirred mixture was placed in an oil bath at 110 ° C for 10 min. The reaction mixture was cooled to ambient temperature and aq. EtOAc (16.5 mL, EtOAc). The reaction mixture was extracted with EtOAc (EtOAc) (EtOAc. The residue was purified by silica gel chromatography eluting with 49:1 v/v di-methane/methanol containing &lt;RTI ID=0.0&gt;&gt; Benzyloxy-1-benzyloxyindenyl-ethoxy)-phenyl]-tert-butoxycarbonylamino-acetic acid (1.2 g, 80%). HRMS : observed mass of C3〇H35NNa07+: 544.2307 ; calculated mass: 544.2306 〇(3) will contain (R)-[4-(2-benzyloxy-1-benzyloxymethyl-ethoxy)-phenyl A hydrogenation vessel of a solution of -3 -butoxycarbonylamino-acetic acid ruthenium 86 g, 3.57 mmol) in methanol (50 mL) was purified with nitrogen and 10% palladium on carbon (100 mg). The atmosphere above the sterol solution was exchanged for hydrogen and the reaction mixture was vigorously stirred at ambient temperature for 3 Torr. The reaction mixture was filtered through a pad of celite and concentrated in vacuo to give &lt;RTI ID=0.0&gt;&gt; g, 73%), which is of sufficient purity for subsequent use without additional purification. HRMS: observed mass of C16H23NNa07+: 364.1368; calculated mass: 364.1367 〇HRMS: observed mass of C3〇H3()F2N306+: 566.2100; 566.2097 〇128748.doc -159- 200848028 Example 161 (j) Good (4-cyclopropyl-2_fluoro-phenyl)_2_{(R) ice [4_(2_yl-yl)-phenyl) ]2,5--Sideoxymidine small base 3_(cardiomethoxy-phenyl)-propanamide

The fine was prepared by the same method as described in Example 16, except that (1) was replaced with (S)-2-t-butoxycarbonylamino-3_(4-methoxy-phenyl)-propionic acid. (S) 2 苐 dibutoxy-Weiylamino-3-(4-fluoro-phenyl)-propionic acid and (R)-苐 dibutoxy-Wilylamino-{4_[ 2-(Tetrahydro-α-Chen-2-yloxy)-ethoxy]-phenyl}-acetic acid instead of (R)-t-butoxycarbonylamino-[4-(2-hydroxy-1) -Methyl-ethoxy)-phenyl]-acetic acid. Preparation of (R)-di-dibutoxyaminoamino-{4-[2-(tetrahydro-t-butyl-2-yloxy)-ethoxy]-phenyl}- as described in Example 48 Acetic acid. HRMS: Observed mass of C30H31FN3O6+ (M+H+): 548.2180; Calculated mass: 548.2192. Example 162 (S) -7V-(4-cyclopropyl-2-fluoro-phenyl)-2-{(R)-4-[4-(S)-2,3-di-based-dioxy )-phenyl]-2,5-di-oxy-imidazolidine-1-yl}-3-(4-methoxy-phenyl)-propanamide 128748.doc -160- 200848028

Prepared by the same method as described in Example 160 except that (1) was replaced with (S)-2-t-butoxycarbonylamino-3-(4-methoxy-phenyl)-propionic acid. (S)-2-t-butoxycarbonylamino-3-(4-fluoro-phenyl)-propionic acid and 〇i) using (R)·t-butoxycarbonylamino-[4-( (S)-2,2-Dimethyl-[13]dioxolan-4-ylmethoxy)phenyl]-acetic acid (prepared as described in Example 116) was substituted for (R)·Di Di Oxydopylamino-[heart (2-alkyl-1-pyridyl-ethoxy)-phenyl]-acetic acid. HRMS : observed mass of C31H32FN3Na07+ (M+Na+): 600.2112 ; Calculated mass: 600.21 16. Example 163 (28'3 8)-^(4-cyclopropyl_2-fluoro-phenyl)-2-{(foot)_4-[4-(2-hydroxy-ethoxylate)

By using 4-cyclopropyl-2 as described in Example 48,

Preparation of 4-cyclopropyl-2-fluoroanilide··, except for (1) by-preparation of 2-fluoroiodoaniline and 128748.doc-161 - 200848028 (according to D. Wallace and C. Chen, Tetrahedron Lett, 43, 6987 (2002) Procedure for 4-bromo-2-fluoroaniline (19.0 g, 100 mmol) with cyclopropyl decanoic acid (11.3 g, 13 1 mmol), palladium acetate (11) ( 1.12 g, 4·79 mmol), tricyclohexylphosphine (2.8 g, 13.2 mmol) and potassium silicate (74.2 g, 265 mmol) were reacted in toluene (4 mL) and water (30 mL). The mixture was placed in an oil bath at 1 Torr. The underarm was heated for 2 days, cooled, and the liquid was filtered through a diatomaceous earth pad. The residual solid in the reaction vessel was wet-milled with water (2 〇〇 mL) and the suspension was filtered through celite. The aqueous filtrate was extracted once with hexane (1 mL). The dried organic layer was filtered through a pad of silica gel and the pad was washed with &lt;RTIgt; The filtrate was concentrated in vacuo to give a red oil. The red oil was fractionated (Vigreux column, 6 trays). A fraction distilled between 6 and 7 mbar at 65-73 ° C was collected to give 6.8 g (45 mmol, 45%) of 4-cyclopropyl-2-fluoroaniline as a pale yellow liquid. H. NMR (300 MHz, CDC13) δ: 6.69 (m, 3Η)? 3.57 (br.s.5 2Η), 1.79 (m, 1Η), 0.87 (m, 2Η), 0·57 (m, 2Η) ). Step 6: 2-{2-Amino-2-[4-(2-trimethyldecyloxy-ethoxy)-phenyl]-acetamido-based #- at -78 °C (4-Cyclopropyl-2-fluorophenyl)-3-phenylbutyridinamine (680 mg, 1.2 mmol) and pyridine (3 mL) were dissolved in dichloromethane (60 mL). A solution of diphosgene (296 mg, 1 mmol) in dichloromethane (15 mL) was added dropwise to this mixture. The mixture was allowed to slowly warm to room temperature and stirred at room temperature overnight. The mixture was allowed to cool in an ice bath and 3 M EtOAc (60 mL) was slowly weighed. (3) Stirring was continued for 3 minutes. The organic layer was separated and dried over anhydrous sodium sulfate and concentrated to give 15 () mg of oily solids, 128 748. doc - 162 - 200848028 by gelatin chromatography (65% v/v Ethyl acetate in alkane) afforded 7V-(4-cyclopropyl-2-fluoro-phenyl)-2-{4-[4-(2- <RTIgt; Base 2,5,5-di-oxy-imidazolidin-1-yl}-3-phenyl-butanamine (7 〇 mg, 0.13 mmol, 13%) HRMS : observed mass of C30H31FN3O5+ (M+H+) : 532.2244 ; 5 Calculated mass: 532.2242. Example 164

(S)-TV-(4-cyclopropyl-2-fluoro-phenyl)-2-{(R)-4-[4-(2-hydroxy small methylethyloxy)-phenyl]- 2,5-di-oxyl-11-°°°-l-yl}-3-(4-methoxyphenyl)-propionic acid amine

OH was prepared by the same method as described in Example 1 60, except that (1) (S)-2-t-butoxycarbonylamino-3-(4-methoxy-phenyl) was used in Step 1. -propionic acid in place of (S)-2-t-butoxycarbonylamino-3-(4-fluoro-phenyl)-propionic acid and (ii) in step 4 (3-dimethylamino- Propyl)-ethylcarbodiimide hydrochloride is used as a coupling reagent in place of bismuth hexafluorophosphate _benzotriazole-oxime-based N, N, N', N, · four f I Wei. HRMS : observed mass of C31H33FN307+ (M+H+): 578.2295 ; Calculated mass: 578.2297. Example 165 (2S,3S)-7V_(4-cyclopropyl-2-fluoro-phenyl)_2-{(R)-4-[4-(R)-2,3·dihydroxy 128748.doc-163 - 200848028 yl-propoxy)-phenyl]-2,5-di-oxy-imidazolidin-1-yl}-3-phenyl-butanamine

Prepared by the same method as described in Example 160, except that (1) Substituting (2S,3S)-2-tert-butoxycarbonylaminophenyl-butyric acid for (S)-2 in Step 1. -Tertibutoxycarbonylamino-3-(4-fluoro-phenylpropionic acid and (Π) used in step 4 (R)-t-butoxycarbonylamino group _[4_((11)_2 , 2_Dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-acetic acid instead of (r)_second butoxycarbonylamino-{4-[2- (tetrahydro-piperidin-2-yloxy)-ethoxy phenyl phenylacetic acid. Prepared as described in Example 11 4 and using (R)-t-butoxycarbonylamino-[4-( (R)-2,2-Dimethyl-[1,3]dioxolan-4-yloxy)-phenyl]-acetic acid. HRMS: observed mass of C31H33FN306+ (m+h+): 562.2349; Calculated mass: 562.2348. Example 166 (2S, 3S) good (4-cyclopropyl-2-fluoro-phenyl)-2-((r)_4_{4-[2-hydroxy-ethoxy)-ethoxy Base]-benton}-2,5 - one side oxy group 嗦 嗦 π 定 _ ι ι _ ι ι ι ι 醯 醯

128748.doc -164- 200848028 was prepared by the same method as described in Example 165, except that the use of (R) di-butoxymethylamino-(4-{2-[2-(tetrazo) -Phen-2-yloxy)-ethoxy]-ethoxy phenyl phenylacetic acid instead of (R)_t-butoxycarbonylamino-[4-((S)-2,2_ Dimercapto-[1,3]dioxolan-4-ylmethoxy)phenyl]-acetic acid HRMS: observed mass of C32H35FN306+ (M+H+): 576.2504; Calculated mass: 576.2505. 28,3 8)-7\^(4-cyclopropyl-2-fluoro-phenyl)-2-((11)-4-{4-[2-(2-methoxy-ethoxy) -ethoxy]-phenyl}_2,5-di-oxy-imidazolidin-1-yl)_3_phenyl-butylamine

Prepared by the same method as described in Example 165, except that (R)-t-butoxycarbonylamino-{4-[2-(2-methoxy-ethoxy)-ethoxy Substituted phenyl}-acetic acid instead of (R)-t-butoxycarbonylamino-[4_((s)-2,2-dimethyl-[1,3]dioxolan-4-yl Oxy) phenyl]-acetic acid. HRMS : observed mass of C33H37FN306+ (M+H): 59〇·2656 ; calculated mass: 590.2661. HRMS : observed mass of C33H36FN3Na06+ (M+Na+): 612.2475 ; calculated mass: 612.2480. Example 168 128748.doc -165- 200848028 (2S,3S)-7V-(4-cyclopropyl_2-fluoro-phenyl)-2-[(R)-4-(4-methylamine-carbenylmethoxy-phenyl)-2 , 5 · di-oxy-imidazolidin-1-yl &gt; 3-phenyl-butanamine

Prepared by the same method as described in Example 165, except that (R)-t-butoxycarbonylamino-(4-mercaptocarbamoylmethoxy-phenyl)-acetic acid was used instead. (R)_Tertibutoxycarbonylamino-[4-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl] - acetic acid. (R)-Tertibutoxycarbonylamino-(4-mercaptoaminecarmidylmethoxy-phenyl)-acetic acid was prepared as described in Example 9. HRMS : Observed mass of C31H32FN405+ (M+ET) : 559.2354 ; Calculated mass: 559.2351. Example 169 (S)-2-{(R)-4-[4-((R)-2,3-dihydroxy-propoxy)-phenyl]-2,5-di-oxy-imidazole -1-kib 4-methyl-pentanoic acid (4-cyclopropyl-2-fluoro-phenyl)-decylamine

Prepared by the same method as described in Example 165 except that (S)-2-tert-butoxycarbonylamino-4-methyl-pentanoic acid was substituted for (2S,3S)-2-di Monobutoxyamino-3-phenyl-butyric acid. 128748.doc -166- 200848028 HRMS : Observed mass of C27H33FN306+ (M+H+) : 514.2349 ; Calculated quality: 514.2348. Example 170 (8)-2-{(11)-4-[4-((8)-2,3-Dihydroxy-propoxy)-phenyl]-2,5-di-oxy-imidazole -1-yl}-4-methyl-pentanoic acid ('cyclopropyl-2-fluoro-phenyl)-decylamine

This was prepared in the same manner as described in Example 169, except that in the step 4, (R)-t-butoxy-Wilylamino-[4-((R)-2,2-dimethyl -[1,3]dioxolan-4-ylmethoxy)-phenyl]-acetic acid instead of (R)-t-butoxycarbonylamino-[4-((S)-2,2- Dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-acetic acid. By the preparation of (R)-t-butoxycarbonylamino-[4-((S)-2,2-dimethyl-indole,3]dioxolan-4-ylmethoxy Preparation of (R)-Tertibutoxycarbonylamino-[4-((R)-2,2-dimethyl-[1,3]dioxos by the same method as described above for phenyl]-acetic acid Pentocyclo-4-ylindolyloxy)-phenyl]-acetic acid, with the exception of (r)-2,2-dimethyl-1,3-dioxolan-4-methanol instead of (S)- 2,2-Dimethyl-i,3-dioxolan-4-methanol. HRMS : observed mass of C27H32FN3Na06+ (M+Na+) : 536.2164 ; Calculated mass: 536.2167. Example 171 (S)-2-{(R)-4-[4-(2-Hydroxy-1-hydroxymethyl-ethoxy)-phenyl]-2,5-di-oxy-imidazole- 1-yl}-4-methyl-pentanoic acid (4-cyclopropyl-2-fluoro-phenyl)-decylamine 128748.doc -167- 200848028

Prepared by the same method as described in Example 160, except that (1) in step 1, (S)-2-tert-butoxycarbonylamino-4-methyl-pentanoic acid was used instead of (S)- 2-tert-butoxycarbonylamino-3-(4-fluoro-phenyl)-propionic acid and (η) (3-dimethylamino-propylethyl-carbodiimide in step 4) The hydrochloride salt was used as the f coupling reagent instead of the hexafluorophosphoric acid to benzotriazole]. The HRMS: the observed mass of C27H33FN306+ (M+H+): 514.2347; the calculated mass: 514.2348. Example 172 (2S, 3S)-2_{(R)-4-[4-(2-decyloxy-ethoxy)-phenyl]_2,5-di-oxy-imidazole-1-yl}-3-phenyl P-tolyl-butylamine

〇〇 - Hunting was prepared by the same method as described in Example 1, except that (1) 4-methyl-aniline was used instead of 'bromoaniline in the V step and (ii) was used in step 4 (R)- Tributoxycarbonylamino-[4-(2-methoxy-ethoxy)-phenylethylidene substituted for (R)-t-butoxycarbonylamino-(4-methoxy-benzene (E)-T-butoxycarbonylaminomethoxy-ethoxyphenyl]-acetic acid was prepared as described in Example 80. 128748.doc 200848028 HRMS : Observed mass of C29H32N3〇5+ (M+H+): 502.2332 ; Calculation Quality: 502.2337. Example 173 (2S,3S)-7V-(4-ethyl-phenyl)-2-{(R)-4-[4-(2-methoxy-ethoxy)-phenyl]-2, 5-di-oxyl-flavor. Sit-l-yl}-3-phenyl"•butanamine

Prepared using the same procedure as described in Example 1, except that (1) 4-ethyl-aniline was used instead of 4-bromoaniline in step 2 and (ii) (R)·third butoxide was used in step 4. Substituted carbonylamino-[4-(2-methoxy-ethoxy)-phenyl]-acetic acid in place of (R)-t-butoxycarbonylamino-(4-methoxy-phenyl)- Acetic acid. (R)-Tertibutoxycarbonylaminoindole 4-(2-methoxy-ethoxy)-phenyl]-acetic acid was prepared as described in Example 80. HRMS : Observed mass of C3〇H34N305+ (M+H+): 5 16.2489 ; Calculated Quality: 516.2493. Example 174 (2S,3S)-7V-(4-isopropyl-phenyl)-2_{(r)-4-[4-(2-methoxy-ethoxy)-phenyl]-2, 5-tertiary oxy-imidazolidin-1-yl b-3-phenyl-butanamine

128748.doc -169- 200848028 was prepared using the same procedure as described in Example 1, except that (1) 4-isopropyl-aniline was used instead of 4-bromoaniline in step 2 and (ii) was used in step 4. (R)-Secondoxyaminoamino-[4-(2-methoxy-ethoxy)-phenyl]-acetic acid instead of (R)-Tertioxycarbonylamino group _(4_曱oxy-phenyl)-acetic acid. (R)-Tertibutoxycarbonylamino-[4-(2-methoxy-ethoxy)-phenyl]«acetic acid was prepared as described in Example 80. HRMS · Observed mass of C31H36N305+ (M+H+): 530.2646 ; Calculated Mass: 530.2650. Example 175 (28,3 8)-7\^(2-Fluoro-4-methyl-phenyl)-2-{(!1)_4_[4_(2-methoxy-ethoxy)-phenyl -2,5-di-oxy-imidazolium-;u-kib 3-phenyl-butanamine

Prepared using the same procedure as described in Example 1, except that (1) 2-fluoro-4-methyl-phenylamine was used in place of 4-di-aniline in step 2 and (π) was used in step 4 (R)- Second butoxycarbonylamino-[4-(2-methoxy-ethoxy)phenyl]-acetic acid instead of (R)-second butoxycarbonylamino- ('methoxy-phenyl) ) - acetic acid. (R)-Tertibutoxycarbonylamino-[4-(2.methoxy-ethoxy)-phenyl]-acetic acid was prepared as described in Example 80. HRMS : Observed mass of C29H30FN3NaO5+ (M+Na+) : 542.2 〇 56 ; Calculated mass: 542.2061. Example 176 128748.doc -170- 200848028 (SHVt-T-butyl-2-chloro-phenyl)-2-{(R)-4-[4-((R)-2,3-di-dipropionyloxy) Phenyl] 2,5-di-oxy group. Rice bran m}_3_methyl-butylamine

OH

〇H /

Prepared by the same method as described in Example 43, except for (1) using (8) methoxyl-phenylamino) _3, methyl-butyric acid instead of (SWf9-ylmethoxy) Aminoamino)-3-naphthalene-2 depropionic acid, (9) in step 1, using a third butyl I gas-aniline instead of 2-fluoro-4-iodoaniline and (iii) performing the steps as described in Example 114 Steps after 3. LC-MS · Observed mass of C27H35ClN3〇6 (M+H+) : 532 ; Calculated mass: 532 〇Example 177 (2S,3 S)4(4_Ethoxy-2_fluoro-phenyl wide M(R) _4 [4_(2-methoxy-ethoxy)-phenyl]-2,5-one oxy _ imipenone _1-kib 3 phenyl phenylbutanamine

Prepared using the same procedure as described in Example 1, except that (1) 4-ethoxy-2-fluoro-aniline was used in place of 4-bromo- and hydrazin in step 2 and (ϋ) was used in step 4 (R) )-Secondoxyaminoamino-[4-(2-methoxy-ethoxy)-benzene 128748.doc - 171 - 200848028 Acetic acid substitution (R) • Ternoxybutylamino group -(4-Methoxy-phenyl)-ethoxime Prepared as described in Example 80 to prepare (R)-t-butoxycarbonylamino-[4-(2-methoxyethoxyphenyl) _Acetic acid. HRMS · Observed mass of C30H33FN3〇6+: 55〇·2352; Calculated mass: 550.2348. Example 178 (28'3 8) also (2-1-4-isopropoxy-phenyl)-2_{ (11)_Heart [4_(2-methoxy-ethoxy)-styl]-2,5·di-oxy-imidazolidin-1-yl}-3-phenyl-butanamine

Prepared by the same procedure as described in Example 50 except that 2-fluoro-4-isopropoxyaniline hydrochloride was used instead of 2-fluoro-4-iodoaniline. HRMS : Observed mass of C31H35FN306+ (Μ+η+) : 564.2498 ; Calculated mass: 564.2505. Example 179 (2S,3S)-jV-(4-〇丫丁ϋ-1-yl-2-fluoro-phenyl)_2-{(r)-4-[4-(2-methoxy-B Oxy)-phenyl]-2,5-di-oxy-imidazole pyridine-^-diphenyl-butylamine

128748.doc -172- 200848028 was prepared by the same procedure as described in Example 50 except that 4-azetidin-1-yl-2-fluoro-phenylamine was used instead of 2-fluoro-4-iodoaniline. Preparation of 4-azetidin-1-yl-2-fluoro-aniline in the following manner: Azetidine (304 mg, 5.17 mmol) was added to 2-fluoro-4-iodoaniline (1 g, in a flask). 4.14 mmol), a mixture of cuprous iodide (304 mg, 0.21 mmol) and potassium acetate (1.75 g, 8.27 mmol) in ethylene glycol (465 μΐ, 8.27 mmol) and isopropanol (4 mL) in. The flask was sealed and heated to 80 °C for 24 hours. The reaction mixture was taken up in ethyl acetate (5 mL EtOAc)EtOAc. The combined organic extracts were dried <RTI ID=0.0> The oil was purified by silica gel chromatography eluting with 40% v/v in ethyl acetate. The product-containing fractions were combined and concentrated to give 4-σ butyl butyl 1-yl-2-phenylaniline as an orange oil (555 mg, 81% yield HRMS. observed mass of C31H34FN4O5) +H+) ·· 561.2501 ; Calculation quality: 561.2508. Example 180

The exception was that the preparation was carried out by the same method as described in Example 50. 128748.doc -173- 200848028 The conversion as detailed below (step 3a) should be carried out in the sequence before proceeding to step 4. Step 3a: (2S,3S)-2-Amino-#-(2-fluoro-4-carbophenyl)-3-phenyl-butanamine (796 mg, 1.99 mmol), zinc cyanide ( 352 mg, 2.99 mmol), hydrazine-triphenylphosphine palladium (〇) (116 mg, ο” and anhydrous tetrahydrofuran (4 mL) were added to a argon degassed and dried flask. After heating at 8 〇r for 8 hours There is no reaction. 2-Dicyclohexylphosphino-2,_6,-dioxaoxybiphenyl (42 mg, 0.1 mmol) is added to the cooled mixture and the reaction mixture is again heated to 80 ° C for a period of time. After 90 minutes, no reaction still took place. To the cooled mixture was added triethylamine (840 μΐ, 5.99 mmol) and the reaction mixture was heated at 80 ° C for 2 hours without reaction. 2-2-ring Hexylphosphino-2-6-monodecyloxybiphenyl (84 mg, 0.2 mmol) was added to the cooled mixture and did not react after 2 hours at <RTI ID=0.0></RTI> <RTIgt; -2'-bis(diphenylphosphino)-oxime_, binaphthylquinone 25.6 mg, 〇. 2 mmol) and anhydrous toluene (2 mL) were added to the cooled mixture. At 85. After heating under the arm for 40 hours, the reaction mixture was dissolved in ethyl acetate (5 mL) and washed with a 1 N aqueous solution of hydrogen sulfate, saturated aqueous sodium hydrogen carbonate and the aqueous layer was ethyl acetate (2×50 mL ) Back extraction. The combined organic layers were dried over sodium sulfate and concentrated. The crude residue was purified by silica gel chromatography eluting with 5 to 5% 5% v/v of ethyl acetate in hexanes to give a yellow residue (2S, 3S) after concentration of the product containing fractions. 2-Aminocyano-2-fluoro-phenyl)-3-phenylbutanamine (120 mg, 20.2% yield). HRMS : Observed mass of C29H28FN405+ (m+H+): 53 1.2035; Calculated mass: 53 1.2038. Example 181 128748.doc -174- 200848028 (S) j-(4-cyano-2.fluoro-phenyl)-2-{(R)-4-[4-(2-hydroxy-ethoxy)- Styrene]-2,5-di-oxy-imidazolidin-1-yl-3-phenyl-butanamine

It was prepared by the same method as described in Example 4, except that Step 1 was carried out as follows. Step 1: To (S)-2-(9H-burial-9-ylmethoxymethylamino)-3-methyl-butyric acid (2·5 g) at 0 ° C under dry argon atmosphere , 7.37 mmol) and a few drops of N,N-monomethylamine in a solution of methylene chloride (20 mL) were slowly added with dichloromethane (1.3 mL, 14.74 mmol). The mixture was placed in a crucible. The mixture was stirred for 15 minutes under the arm and stirred at room temperature for 2 hours. After removing the solvent, the residue was dissolved in methylene chloride (20 mL) and 4-amino-3-fluoro-bromocarbonitrile (8 40 mg, 6.14 mmol) was added to the obtained solution at 〇 °C. 4, dimethylamino oxime (150 mg, 1.2 mmol) and pyridine (〇·78 mL, 9 21 mm〇1). The mixture was stirred at 〇 ° C for 2 hours and at room temperature overnight. The reaction was quenched with aqueous citric acid and then extracted with dichloromethane (three times). The combined organic extracts were washed with EtOAc EtOAc EtOAc. The residue was purified by silica gel chromatography eluting with a gradient of 1% to dichloromethane to &lt;RTI ID=0.0&gt;&gt; Concentrate the fractions containing the product to give a white solid [[8] small &amp; aryl winter phenylamine ketone 2-methyl-propyl] _ carbamic acid candiyl ketone (2 15 ton , 77. 128748.doc -175- 200848028 LC-MS : C27H25FN3 (V observation quality (M+H+): 458; calculation quality · · 548. LC-MS : C23H24FN4 (V observation quality (M+H+) : 455 ; Calculated mass: 455. Example 182 (2S, 3S) i-(4-Ethyl-2-fluoro-phenyl)-2·{(Ι^255-di- oxy-4-[4- (2-Sideoxy-2-bar-u-pyridyl-buyl-ethoxy)-styl]-imidazolidinyl}-3_phenyl-butanamine

Prepared by the same procedure as described in Example 145, wherein the compound was obtained as a by-product during the purification of step 6. HRMS : Observed mass of C33H34FN4〇6+ (M+H+) : 601·2454 ; Calculated mass: 601.2457. Method used in biological examples Cell viability assay as a cell viability index of cell respiration by desertification 3-(4,5-dimethylthiasin-2-yl)·2,5-diphenyl The tetrazolium (mtt) was reduced to formazan and measured. The ΗΤ-29 cells were maintained in McCoy 5a medium (modified) containing 1% fetal bovine serum and inoculated into a 96-well microtiter plate at 2000 cells per well in a volume of 1 μm, while mda was -MB- 128748.doc -176- 200848028 468 cells were maintained in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum and seeded at 4000 cells per well in a volume of 1 μμΐ In a 96-well microtiter plate. On the next day, the cells were exposed to additional 丨00 4 compounds at the indicated concentrations and cultured for 5 days. After adding 50 μl of each well to a 5 mg/ml MTT stock solution in Dubecco's phosphate buffered saline (PBS), the cells were at 37. Replanting

2.5 hours. Thereafter, the medium was removed and 5 y y 1 〇〇 % ethanol was added to each well to dissolve the formazan crystals. Living cells converted sputum to formazan by evaluation at 570 nm with a micro-disc reader. Results are provided as a percentage of the viability of the untreated cells (control), which is considered to be 100% viable. Analysis of the combined effects of the two drugs using the method described by Chou and Talalay in Advances &amp; Regulation, Vol. 22, pp. 27-55 (1984), treated with the computer software CalCUSyn (BIOSOFT, CambHdge, υκ), the two drugs Dose-response interactions (antagonism, additive, and synergistic effects) are expressed as &amp; CI (scores, which are the fractions affected by the combination index). This program provides an objective computer evaluation program. For drugs that have a completely independent mode of action that are not mutually exclusive, 'Cl q ' is called &gt;; [representing synergy, additive effects, and antagonism, respectively. This information is confirmed by a typical equivalence diagram made by the same program. The isobologram can be generated for different effects, such as ED50, ED70, and ED90. If the f(4)乂 combination data point falls on the diagonal when it is produced under ED5, it indicates the additive effect; if it falls to the lower left, it indicates synergy; and if it falls to the upper right, it indicates the antagonistic effect. effect. If the mono-drug is not very effective and the heart cannot be obtained, then 128748.doc 177- 200848028 can not be given i, the result Fa-CI or the equivalent line graph. In this case, the results are presented in a typical dose response diagram. Example 183 - Erlotinib and ]&gt;11:1&lt;: In vitro combined effect of inhibitors in human cancer cells. Human MDA-MB-468 breast cancer cell lines overexpress eGFr, and thus its proliferation against erlotinib Single agent treatment is relatively sensitive. After treatment of these cells with hydrazine, hydrazine, significant growth inhibition was observed in vitro. A significantly lower growth inhibitory effect was observed after treatment with the same cell strain I of Example 56. Mutations in tumor cells have been reported to predict sensitivity to mek inhibition. The modest effect of the compound of Example 56 on MDA_MB-468 is sufficiently correlated with the fact that the strain (4) has wild type (10) and _ genes. In the combination assay of the two agents, the erlotinib and the compound of Example 56 are simultaneously (added on the first day) or successively (added on the next day and the second day respectively) to the cells, On the 5th, cell viability was measured by MTT assay, and the results were analyzed using CalcuSyn software. As shown in Fig. a, when the combined effect Fa &gt; 40%, the synergistic effect of the two drugs was observed regardless of the treatment time course (CI &lt; 1). In addition, when the results are shown in the equivalent line diagram (Figs. a, c, D), the doses of the compound ED", ED?5, ΕΙ^ and erlotinib ED50, ED75, ED9 of Example 56 are plotted separately. On the x-axis and &quot;from the top, the combined data points of Fa fall to the lower left of the diagonal, indicating the synergy of the two drugs for all three treatment schedules at all dose levels. ^ Under the line of sight As shown in the table, the software calculation combination index (ci) values are extremely significant (&lt;〇·5). Two other compounds are used (example 11 * characters (Figures 2A, B, C, D) and Example 48 Compounds (Fig. 3 A, Br l, D)) observed 128748.doc -178- 200848028 to similar results. These synergistic results indicate MEK inhibitors, and in particular the substitution of substituted carbamazepines disclosed herein. The agent can be combined with erlotinib to provide efficacy in a broader patient population. Human ΗΤ-29 colorectal cancer cells with brav mutations are sensitive to MEK inhibitors treated with a single agent. However, these cells are errodin Nie is extremely resistant (even at a drug concentration of > 30 μΜ) ED^). When the same cells are treated with erlotinib in the presence of low dose MEK inhibitors (compounds of Example 56, compounds of Example 114 or compounds of Example 48), regardless of erlotinib and MEK inhibitor compounds Synergistic effects were observed at the same time or sequentially (Figures 4, 5 and 6, respectively). These results represent MEK inhibitors (especially substituted beta-urea urea MEK inhibitors, such as the MEK inhibitors disclosed herein) Possible combination of treatment with erlotinib (for example, a pharmaceutical product such as Tarceva®) in a cancer population resistant to erlotinib. [Simplified illustration] Figure 1: Erlotinib And Example 48 anti-proliferative effects in human MDA-MB-468 breast cancer cells. A) Fa-CI curve. B) Equivalent line graph (at ED75) Figure 2: Erlotinib and Example 56 in human mda -MB-468 anti-proliferative effect in breast cancer cells. A) Fa-CI curve. B) Equivalent line graph (at ED75) Figure 3 · Erlotinib and Example ι14 in human mda-MB-468 breast cancer cells Anti-proliferative effect in the middle. A) Fa-CI curve. B) Equivalent line graph (at ED75) Figure 4 · Ero And the effect of Example 48 on human ht-29 colorectal cancer cells. Five-day assays were performed as described in Materials and Methods. 128748.doc -179- 200848028 Figure 5: Erlotinib and Example 56 Anti-proliferative effect in human HT-29 colorectal cancer cells. Five-day sputum assay as described in Materials and Methods. Figure 6: Resistance of erlotinib and Example 114 in human ΗΤ-29 colorectal cancer cells Proliferative effect. Five days of diced dicing was performed as described in Materials and Methods. Figure 7: Anti-proliferative effect of erlotinib and Example 48 in human BxPC-3 pancreatic cancer cells. A) Fa-CI curve. B) Equivalent line graph (at ED75). Figure 8: Anti-proliferative effect of erlotinib and Example 56 in human Bχpc_3 pancreatic cancer cells. A) Fa-CI curve. B) Equivalent line graph (at ΕΕ &gt; 75). Figure 9: Fa-CI curve of erlotinib and Example 114 in human sputum (%3·adenocarcinoma cells). B) Equivalent line graph (at ED75). 128748.doc -180-

Claims (1)

200848028 X. Patent application scope: 1 · erlotinib (erl〇tinib) and MEK inhibitors for the preparation of drugs suitable for tumor cell proliferation p » 上上条物 can be used to contain # specific tumor The cells are sequentially or simultaneously contacted with a quantitative amount of erlotinib and a certain denier inhibitor compound, wherein the amounts are effective to synergistically inhibit proliferation of the tumor cells in a combined form. 2. If the requester uses it, the MEK inhibitor compound is of the formula [Human: ^ f % Wherein: R1 is selected from the group consisting of bromine, iodine, ethynyl, cycloalkyl, alkoxy, decyl, decyl, heterocyclic, cyano, linear alkyl and branched alkyl R2 is selected from the group consisting of hydrogen, chlorine, fluorine and alkyl; R3 is selected from the group consisting of hydrogen and fluorine; R is selected from hydrogen, optionally substituted aryl, optionally substituted heteroaryl a group consisting of an alkyl group and a cycloalkyl group; R5 is selected from the group consisting of hydrogen and a group: wherein R6 is selected from the group consisting of a hydroxyl group, an alkoxy group, a cycloalkyl group, a trihaloalkyl group, and a view 128748.doc 200848028 f a group of substituted aryl groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups; R&amp;R is independently selected from the group consisting of hydrogen, alkyl and tri-alkyl Or R6 and R7 may together form a cycloalkyl group and R8 is hydrogen; and a pharmaceutically acceptable salt or ester thereof. 3. \ / As claimed in claim 1, wherein the MEK inhibitor compound is a compound of formula J: R4 I wherein: R1 is selected from the group consisting of bromine, iodine, ethynyl, cycloalkyl, alkoxy, butyl butyl, ethyl hydrazino, heterocyclic, cyano, linear alkyl and branched alkyl. Group R; is selected from the group consisting of hydrogen, gas, fluorine and alkyl; R3 is selected from the group consisting of hydrogen and fluorine; and r4 is selected from hydrogen, optionally substituted aryl, alkyl and cycloalkyl. The group of r5 is selected from the group consisting of hydrogen and the following groups: R6-C-R8 17 R7 wherein R6 is a free hydroxy group, an alkoxy group, a cycloalkyl group, a trihaloalkyl group, an alkane 128748.doc 200848028, a group of optionally substituted aryl and optionally substituted heteroaryl; R and R8 are independently selected from the group consisting of hydrogen, alkyl and trihaloalkyl; or R6 and R7 may together form a cycloalkane And R8 is hydrogen; and a pharmaceutically acceptable salt or ester thereof. 4. The use of the claim item, wherein the formula has the following formula: Wherein: R is selected from the group consisting of bromine, iodine, ethynyl, cycloalkyl, alkoxy, ethyl sulfonyl, thiol, heterocyclyl, cyano, linear lower alkyl and branched lower alkyl a group of R2 selected from the group consisting of hydrogen, gas, fluorine, and a lower alkyl group; R is selected from the group consisting of hydrogen and fluorine; and R is selected from an aryl group, a lower alkyl group, and a ring which are optionally substituted. a group consisting of alkyl groups; R is selected from the group consisting of hydrogen and the following groups: R6--C-r8 I R7 wherein R6 is selected from the group consisting of hydroxyl, alkoxy, cycloalkyl, trihalo-lowerane 128748.doc 200848028 A low-area, optionally substituted aryl group and optionally substituted heteroaryl group; selected from the group consisting of hydrogen, a lower alkyl group and a tridentate low carbon yard R7 and R8 Or R and R7 may together form a cycloalkyl group and R8 is hydrogen; and a pharmaceutically acceptable salt or vinegar thereof. 5. The use of claim 4, wherein Ri is selected from the group consisting of iodine and ethynyl groups. f Fluorine composition 6. The use of the item 5, wherein R2 is selected from the group consisting of hydrogen, chlorine and a group. 7. The use of claim 6 wherein r3 is hydrogen. 8. The use of claim 7, wherein R6-C-R8 and R7 and R8-integrated ^·^ are independently selected from the group consisting of hydrogen and methyl. 9 · If the request item 8 ▲ 贞 8 is used in the 'where r4 is replaced by the situation as the case is 10 · If the eye is 9 A 1 soil, attack,,, and R is selected from the following: E and B; έ和士, ^ u 暴暴, and a small suspension, and the group, R2 is selected from the group consisting of hydrogen, R4 hair, flying squirrels and sputum, R3 is R is phenyl substituted as appropriate, ... is R6 —C —- R 8 is a f group and R 8 is a hydrogen. R 6 is optionally substituted phenyl, 128 748. doc 200848028 η. The use of claim 10, wherein R 4 is alkoxy substituted phenyl. 12. The use of claim η, wherein R1 is iodine and r2 is selected from the group consisting of chlorine and fluorine. 13. The use according to claim 12, wherein R6 is phenyl and 4 is a phenyl group substituted with a member selected from the group consisting of 2, hydrazine- 3⁄4 oxy and 2-hydroxy-ethoxy. The use of the formula 1 wherein the compound of the formula I is selected from the group consisting of: (2S, 3S)-N-(4-actyl-phenyl)-2_[(R)-4 -(4_methoxy-phenyl)·2,5-di-oxy-imidazolidin-1-yl]-3-phenyl-butanamine; (28,3 8)-&gt;1-(4 -A-phenyl)-2-[(11)-4-(4-methoxy-phenyl)-2,5-di-oxy-imidazolidin-1-yl]-3-phenyl-butyl Indoleamine; (2S,3S)-N-(4-ethynyl-fluoro-phenyl)-2-{(R)-4-[4-(2-hydroxy-ethoxy)-phenyl]-2 , 5-tertiary oxy-myroxy-1-yl}-3-phenyl-butanamine; (2R,3S)-N-(4-ethylfastyl-2-a-phenyl)-2 -{(R)-4-[4-(2-trans)-ethoxy)-phenyl]-2,5-di-oxy-imidazolidin-1-yl}-3-phenyl-butane Amine; (2S,3S)-N-(2-chloro-4-bromo-phenyl)-2,{(R)-4-[4-(2-trans-ethyl-ethyl)-phenyl]- 2,5-di-oxyl-flavor. Sitting bite-1_yl}-3-phenyl-butylamine '(28,3 8)-2-{(11)-4-[4-(2-hydroxy-ethoxy)-phenyl]- 2,5-di- oxy-flavor σ sitt-t-decyl-1 -yl} - N - ( 4 - moth-2-mercapto-yl)-3 -phenyl-butyl &amp;&amine' 2S,3S)-N-(2-Chloro-4-iodo-phenyl)-2-{(R)_4_[4_((R)_2,3_diheptyl-propoxy)phenyl]- 2,5-di-oxy-imidazolidin-1-yl}-3-phenyl-butanamine; 128748.doc 200848028 (2S,3S)-N-(2-chloro-4-iodo-phenyl) -2-{(R)-4-[4-((S)-2,3-dihydroxy-propoxy)-phenyl]-2,5-di-oxyl-flavored bite&&;1-yl}-3-phenyl-butanamine; (2S,3S)-2-{(R)-2,5-di- oxy-4-[4-(2- oxo-2- Ethrolidin-1-yl-ethoxy)-phenyl]-imidazolidin-1-yl}-N-(2-fluoro-4-iodo-phenyl)-3-phenyl-butylamine; 28,3 8)-2-((1〇-2,5-di-oxy-4-thiophen-3-yl-imidazolidine-1-yl)-N-(4-iodo-phenyl)-3 -phenyl-butanamine; (S)-2-[(R)-4-(2,3-dihydro-benzo[1,4]dioxol-6-yl)-2,5- Bis-oxy-imidazolidin-1-yl]-N-(2-fluoro-4-iodo-phenyl)-3-phenyl-propanamide; (S)-2-[(R)-4- (4-acetamido-phenyl)-2,5-di-oxy-imidazole -1-yl]·Ν-(2-fluoro-4-iodo-phenyl)-3-phenyl-propanamine; (4-{(R)-l-[(lS,2S)-l-(( 2-fluoro-4-iodo-phenylamine indenyl)-2-phenyl-propyl]-2,5-di-oxy-imidazolidin-4-yl}-phenoxymethyl)-phosphine Dimethyl phthalate; (2S,3S)-N-(2-defy-4-moth-phenyl)-2-((R)-4-isopropyl-2,5-di-oxyl---咬-丨-yl)-3-phenyl-butyric acid amine, (S)-N-(2-fluoro-4-iodo-phenyl)-2-{(R)-4-[4-(2- Hydroxy-ethoxy)-phenyl]-2,5-di-oxy-imidazolidin-1-yl}-3-methyl-butanamine; (S)-N-(2-fluoro-4- Iodine-phenyl)-2_[(R)-4-(4-methoxy-phenyl)-2,5-di-oxy-imidazolidine-1-yl]-3-o-indolephenyl-propane Indoleamine; (S)-N-(2-fluoro-4-iodo-phenyl)-2-[(R)-4-(4-methoxy-phenyl)-2,5-di-oxyl -imidazridin-1-yl]-3-m-tolyl-propionamide; 128748.doc -6- 200848028 (S&gt;N-(2·fluoro-4-iodo-phenyl)-2-[(R) 4-(4-methoxyphenyl)_2,5-di-oxy-imidazolidine-1-yl]-3-p-tolyl-propionamide; and (S)-N-(4-ring Propyl-2·fluoro-phenyl)-3-(4-fluoro-phenyl&gt;2-oxime (R&gt;4_[4 (2-~yl_&gt;1_ thiol-ethoxy)_ Phenyl]-2,5-di-side oxygen - taste. Sit bite · 1 · kiprofen. 15. / 16. For the use of the claimed item, wherein the compound of formula j is selected from the group consisting of: (28'38)-]^-(2-fluoro-4-de-phenyl)-2 -{(11)-4-[4-(2-light-based-ethoxyl-phenyl]-2,5-di-oxy-imidazolidin-1-yl-3-phenyl-butanamine (2S,3S)-2-{(R)-4-[4-((R)-2,3-dihydroxy-propoxy)-phenyl 2,5-di-oxy-imidazole-丨_基}_n-(2-Fluoro-4-iodo-phenyl)_3_phenyl_butanamine; (2S,3S)-N-(2-Ga-4-iodo-phenyl)-2- {(R)-4-[4-((R)-2,3&lt; _ yl-propoxy)-phenyl]-2,5-di-oxy--salt. Guanidine; (2S,3S)-N-(2-chloro-4-iodo-phenyl)-2-{()-4-[4-(〇2,3-di-yl-propoxy) -phenyl]-2,5-di- oxy- miso bite-^ kibene phenyl melamine; and (2S,3S)-N-(4-cyclopropyl-2-fluoro-phenyl gt ; 2-{(r)_444々h ethoxy)-phenyl]-2,5-di- oxy-m-sodium sulphate Use of a compound of I for the preparation of a medicament suitable for inhibiting the growth of tumor cells resistant to erlotinib, which may be used to include such swelling Cells sequentially or simultaneously with a method of once a San, do ~ ® piece goods on the Herault 128748.doc 200848028 Nepal and quantitation of the said compound of formula 1 and its pharmaceutically acceptable salt or ester thereof in contact: Wherein: R is selected from the group consisting of bromine, iodine, ethynyl, cycloalkyl, alkoxy, ethyl sulfonyl, thiol, heterocyclic, cyano, linear lower alkyl and branched low carbon a group consisting of: r2 is selected from the group consisting of hydrogen, gas, fluorine, and a lower alkyl group; R is selected from the group consisting of hydrogen and fluorine; and R is selected from the group consisting of an optionally substituted aryl group, a lower alkyl group, and a group consisting of cycloalkyl groups; R is selected from the group consisting of hydrogen and the following groups: R6 - C - R8 17 R7 wherein R6 is selected from the group consisting of hydroxyl, alkoxy, cycloalkyl, trihalo lower alkyl a group of a lower fluorenyl group, an optionally substituted aryl group, and optionally a substituted heteroaryl group; R and R8 are independently selected from the group consisting of hydrogen, a lower alkyl group, and a trihalogen lower alkyl group. Or R6 and R7 may together form a cycloalkyl group and R8 is hydrogen; 128748.doc 200848028 wherein the equal amounts are effective to synergistically inhibit the proliferation of such tumor cells in combination. 1 7. Use of an erlotinib and a compound of the formula for the preparation of a medicament suitable for inhibiting the growth of tumor cells resistant to one or more MEK inhibitors, the medicaments being useful for the inclusion of such tumor cells In a method of contacting erlotinib and a certain amount of the quinone compound and a pharmaceutically acceptable salt or ester thereof in sequence or simultaneously: R4 wherein: R is selected from the group consisting of bromine, iodine, ethynyl, cycloalkyl, alkoxy, acetonide V group, heterocyclic group, cyano group, linear low alkyl group and branched low carbon alkyl group a group selected from the group consisting of hydrogen, chlorine, fluorine, and a lower alkyl group; R is selected from the group consisting of hydrogen and fluorine; and R is selected from an aryl group, a lower alkyl group, and a ring which are optionally substituted. The alkyl group is selected from the group consisting of: hydrogen is selected from the group consisting of hydrogen and the following groups: R6-C-_r&gt;8 IR R7 wherein R6 is selected from the group consisting of a hydroxyl group, an alkoxy group, a cycloalkyl group, a trihalogenated lower alkane. 128748.doc 200848028 Groups of benzyl, lower alkyl, optionally substituted aryl and optionally substituted heteroaryl; R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl and tridentate low carbon a group of alkyl groups; or R6 and R7 may together form a cycloalkyl group and R8 is hydrogen; wherein the equal amounts are effective to synergistically inhibit the proliferation of such tumor cells in combination. 18. The use of erlotinib and a MEK inhibitor for the preparation of a medicament suitable for inhibiting the growth of tumor cells in a human, the medicament being useful for comprising administering to the human a sequential or simultaneous administration of a certain amount of erlotinib And a method of administering a quantity of the MEK inhibitor compound, wherein the equal amounts are effective to synergistically inhibit proliferation of the tumor cells in a human in vivo. 19. The use of claim 18, wherein the MEK inhibitor compound is of the formula "Compound: Wherein: Rl is selected from the group consisting of bromine, iodine, ethynyl, cycloalkyl, alkoxy, ethyl sulfonyl, thiol, heterocyclic, cyano, linear lower alkyl and branched low carbon alkyl Group R; R is selected from the group consisting of hydrogen, gas, fluorine and low carbon alkyl; R is selected from the group consisting of hydrogen and fluorine; 128748.doc -10- 200848028 R4 is selected from aryl groups which are optionally substituted a group consisting of a low carbon alkyl group and a cycloalkyl group; R5 is selected from the group consisting of hydrogen and the following groups: R6-C-R8 17 R7 wherein R6 is selected from the group consisting of a hydroxyl group, an alkoxy group, a cycloalkyl group, and a third group. a group of a halo lower alkyl group, a lower alkyl group, an optionally substituted aryl group, and optionally a substituted heteroaryl group; R7 and R8 are independently selected from the group consisting of hydrogen, a lower alkyl group, and a trihalogen low carbon. a group of alkyl groups; or R6 and R7 may together form a cycloalkyl group and R8 is hydrogen; and a pharmaceutically acceptable salt or ester thereof. 20. Use of an erlotinib and a MEK inhibitor for the preparation of a medicament for inhibiting the growth of tumor cells in a human, wherein the tumor cells are resistant to one or more MEK inhibitors, the medicaments being useful A method comprising administering to a human a sequential or simultaneous administration of a certain amount of erlotinib and a quantity of a mek inhibitor compound, wherein the equal amount is effective to synergistically inhibit proliferation of the tumor cells in a human. 21. The use of claim 20, wherein the antimony inhibitor compound is a compound: 128748.doc 200848028 wherein: is a free bromine, moth, ethynyl, cycloalkyl, alkoxy, ethyl, azeocyclyl, heterocyclyl, cyano, linear lower alkyl and branched lower carbon a group consisting of a base group; 2 R is selected from the group consisting of hydrogen, gas, fluorine, and a lower alkyl group; R is selected from the group consisting of hydrogen and fluorine; and R is selected from an aryl group optionally substituted with a low carbon. a group consisting of an alkyl group and a cycloalkyl group; R is selected from the group consisting of hydrogen and a group: R6—C—R8 17 R7 wherein R is selected from the group consisting of a hydroxyl group, an alkoxy group, a cycloalkyl group, and a trihalogenated lower alkane. a group consisting of a low-carbon alkyl group, an optionally substituted aryl group, and optionally a substituted heteroaryl group; R and R are independently selected from the group consisting of hydrogen, a low carbon alkyl group, and a trihalogen low carbon alkyl group. a group; or R6 and R7 may together form a cycloalkyl group and R8 is hydrogen; and a pharmaceutically acceptable salt or ester thereof. 22. Use of erlotinib and a MEK inhibitor for the preparation of a medicament suitable for inhibiting the growth of tumor cells in a human, wherein the tumor cells are resistant to erlotinib, and the medicaments can be used to contain A method in which humans are sequentially or simultaneously π with an amount of erlotinib and a certain amount of a MEK inhibitor compound, wherein the equal amounts are effective in synergistic inhibition of humans in combination 128748.doc -12-200848028 Proliferation of tumor cells. 23. The use of claim 22, wherein the MEK inhibitor compound is a compound: Wherein: R1 is selected from the group consisting of bromine, iodine, ethynyl, cycloalkyl, alkoxy, acetamethylene, fluorene, L-heterocyclyl, cyano, linear low carbon alkyl and branched lower alkyl a group of R free radicals consisting of hydrogen, chlorine, fluorine, and a lower alkyl group; R is selected from the group consisting of hydrogen and fluorine; aryl, lower alkyl, and naphthenic substituted by free-form conditions a group consisting of: R5 is selected from the group consisting of hydrogen and the following groups: R6 - C - R8 wherein R6 is selected from the group consisting of ώ 红 red base, alkoxy, cycloalkyl, trihalo lower alkyl low stone a group consisting of an anodic group, an i-unit, a substituted aryl group, and optionally a substituted heteroaryl group; R and R8 are 3® &gt; ϊ I , , independently selected from hydrogen, low a group consisting of a carboalkyl group and a trihalo lower alkyl group; or 128748.doc -13 - 200848028 R6 and R7 may together form a cycloalkyl group and R8 is hydrogen; and a pharmaceutically acceptable salt or ester thereof. f i 128748.doc 14-